Carboxamide compounds and their use as calpain inhibitors

ABSTRACT

The present invention relates to novel carboxamide compounds and their use as a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity and to a method for the therapeutic and/or prophylactic treatment by administering an effective amount of at least one of these carboxamide compounds. 
     The carboxamide compounds are compounds of the general formula I 
     
       
         
         
             
             
         
       
     
     in which
 
W—R 2  is selected from
 
     
       
         
         
             
             
         
       
     
     and R 1 , R 2 , R 3a , R 3b , Y 1 , Y 2 , Y 3 , Y 4 , X, Q, m, k, R w  and R w*  have the meanings mentioned in the claims, the tautomers thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein Y 1 , Y 2 , Y 3  and Y 4  are CR y , or one or two of the variables Y 1  to Y 4  are a nitrogen atom and the remaining variables are CR y , wherein the radicals R y  may be identical or different and have the meanings mentioned in the claims.

CROSS-REFERENCE TO RELATED APPLICATIONS

This claims the benefit of U.S. Provisional Patent Application Nos.61/154,118, filed Feb. 20, 2009 and 61/289,772, filed Dec. 23, 2009, thecontents of all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel carboxamide compounds and theiruse for the manufacture of a medicament. The carboxamide compounds areinhibitors of calpain (calcium dependant cysteine proteases). Theinvention therefore also relates to the use of these carboxamidecompounds for treating a disorder associated with an elevated calpainactivity.

BACKGROUND OF THE INVENTION

Calpains are intracellular, proteolytic enzymes from the cysteineprotease group and are found in many cells. The enzyme calpain isactivated by elevated calcium concentration, with a distinction beingmade between calpain I or μ-calpain, which is activated by μ-molarconcentrations of calcium ions, and calpain II or m-calpain, which isactivated by m-molar concentrations of calcium ions. Currently, furthercalpain isoenzymes are also postulated (M. E. Saez et al.; DrugDiscovery Today 2006, 11 (19/20), pp. 917-923; K. Suzuki et al., Biol.Chem. Hoppe-Seyler, 1995, 376 (9), pp. 523-9).

Calpains play an important role in various physiological processes.These processes include the cleavage of different regulatory proteinssuch as protein kinase C, cytoskeletal proteins such as MAP 2 andspectrin, and muscle proteins, protein degradation in rheumatoidarthritis, proteins in the activation of platelets, neuropeptidemetabolism, proteins in mitosis, and others which are listed in: M. J.Barrett et al., Life Sci. 1991, 48, pp. 1659-69; K. Wang et al., Trendsin Pharmacol. Sci. 1994, 15, pp. 412-419.

Elevated calpain levels have been measured in various pathophysiologicalprocesses, for example: ischemias of the heart (e.g. myocardialinfarction), the kidney, the lung, the liver or the central nervoussystem (e.g. stroke), inflammations, muscular dystrophies, cataracts ofthe eyes, diabetes, HIV disorders, injuries to the central nervoussystem (e.g. brain trauma), Alzheimer's, Huntington's, Parkinson'sdiseases, multiple sclerosis etc. (see K. K. Wang, above) and infectiousdiseases such as malaria (I M Medana et al., Neuropath and Appl.Neurobiol. 2007, 33, pp. 179-192). It is assumed that there is aconnection between these diseases and generally or persistently elevatedintracellular calcium levels. This results in calcium-dependentprocesses becoming hyperactivated and no longer being subject to normalphysiological control. A corresponding hyperactivation of calpains canalso trigger pathophysiological processes.

For this reason, it was postulated that inhibitors of calpain could beof use for treating these diseases. This postulate was confirmed by avariety of investigations. Thus, Seung-Chyul Hong et al., Stroke 1994,25 (3), pp. 663-669, and R. T. Bartus et al., Neurological Res. 1995,17, pp. 249-258, have demonstrated that calpain inhibitors have aneuroprotective effect in acute neurodegenerative impairments orischemias such as occur after cerebral stroke. K. E. Saatman et al.,Proc. Natl. Acad. Sci. USA, 1996, 93, pp. 3428-3433 describe thatfollowing experimental brain trauma, calpain inhibitors also improvedrecovery from the memory performance deficits and neuromotorimpairments. C. L. Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995,92, pp. 7662-6, found that calpain inhibitors have a protective effecton hypoxia-damaged kidneys. Yoshida, Ken Ischi et al., Jap. Circ. J.1995, 59 (1), pp. 40-48, pointed out that calpain inhibitors hadfavorable effects following cardiac damage which was produced byischemia or reperfusion. The calpain inhibitor BDA-410 delayed theprogression of malaria infection in a mouse model of malariapathogenesis as shown by X. Li et al., Mol. Biochem. Parasitol. 2007,155 (1), pp 26-32.

More recent studies have shown in calpastatin transgenic animals thatthe expression of the natural inhibitor of calpain significantlyattenuates the pathophysiological effects of activated calpain inexperimental glomerulonephritis shown by J. Peltier et al., J. Am. Soc.Nephrol. 2006, 17, pp. 3415-3423, in cardiovascular remodeling inangiotensin II-induced hypertension, in impaired synaptic transmissionin slow-channel congenital myasthenic syndrome shown by J. S. Groshonget al., J. Clin. Invest. 2007, 117(10), pp 2903-2912, in excitotoxic DNAfragmentation via mitochondrial pathways shown by J. Takano et al., J.Biol. Chem. 2005, 280 (16), pp. 16175-16184, and in necrotic processesin dystrophic muscles shown by M. J. Spencer et al., Hum. Mol. Gen.,2002, 11(21), pp. 2645-2655.

It has been shown in recent years that both the function and themetabolism of a number of important proteins involved in the developmentof Alzheimer's disease are modulated by calpain. Various externalinfluences such as, for example, excitotoxins, oxidative stress or elsethe action of amyloid protein lead to hyperactivation of calpain in thenerve cell, causing, as cascade, a dysregulation of the CNS-specifickinase cdk5 and subsequently a hyperphosphorylation of the so-called tauprotein. Whereas the actual task of the tau protein consists ofstabilizing the microtubules and thus the cytoskeleton, phosphorylatedtau is no longer able to fulfil this function; the cytoskeletoncollapses, axonal transport of matter is impaired and thus eventuallythe nerve cell degenerates (G. Patrick et al., Nature 1999, 402, pp.615-622; E. A. Monaco et al.; Curr. Alzheimer Res. 2004, 1 (1), pp.33-38). Accumulation of phosphorylated tau additionally leads to theformation of so-called neurofibrillary tangles (NFTs) which, togetherwith the well-known amyloid plaques, represent a pathological hallmarkof Alzheimer's disease. Similar changes in the tau protein, generallyreferred to important feature of as tauopathies are also observed inother (neuro)degenerative disorders such as, for example, followingstroke, inflammations of the brain, Parkinsonism, in normal-pressurehydrocephalus and Creutzfeldt-Jakob disease.

The involvement of calpain in neurodegenerative processes has beendemonstrated in transgenic mice with the aid of calpastatin, a specificand natural inhibitor of calpains (Higuchi et al.; J. Biol. Chem. 2005,280 (15), pp. 15229-15237). It was possible with the aid of a calpaininhibitor to reduce markedly the clinical signs of acute autoimmuneencephalomyelitis in a mouse model of multiple sclerosis (F. Mokhtarianet al.; J. Neuroimmunology 2006, Vol. 180, pp. 135-146). It has furtherbeen shown that calpain inhibitors on the one hand block the Ab-induceddegeneration of neurons (Park et al.; J. Neurosci. 2005, 25, pp.5365-5375), and in addition reduce the release of the β-amyloidprecursor protein (β APP) (J. Higaki et al., Neuron, 1995, 14, pp.651-659). With this background, calpain inhibitors having sufficient CNSavailability represent a novel therapeutic principle for the treatmentof neurodegenerative disorders in general and in particular also ofAlzheimer's disease.

The release of interleukin-1α is likewise inhibited by calpaininhibitors (N. Watanabe et al., Cytokine 1994, 6(6), pp. 597-601). Ithas additionally been found that calpain inhibitors show cytotoxiceffects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass. BreastCancer Res., Sendai Jp, 1994, 25.-28. Sep., Int. J. Oncol. S(Suppl.),1994, 381).

The involvement of calpain in HIV disorders has only recently beenshown. Thus, it has been demonstrated that the HIV-induced neurotoxicityis mediated by calpain (O'Donnell et al.; J. Neurosci. 2006, 26 (3), pp.981-990). Calpain involvement in the replication of the HIV virus hasalso been shown (Teranishi et al.; Biochem. Biophys. Res. Comm. 2003,303 (3), pp. 940-946).

Recent investigations indicate that calpain plays a part in so-callednociception, the perception of pain. Calpain inhibitors showed adistinctly beneficial effect in various preclinically relevant models ofpain, e.g. in the thermally induced hyperalgesia in rats (Kunz et al.;Pain 2004, 110, pp. 409-418), in Taxol-induced neuropathy (Wang et al.;Brain 2004, 127, pp. 671-679) and in acute and chronic inflammatoryprocesses (Cuzzocrea et al.; American Journal of Pathology 2000, 157(6), pp. 2065-2079).

The involvement of calpain in the development of kidney diseases, suchas chronic kidney diseases, e.g. diabetic nephropathy, has also beenshown recently. Thus, it has been demonstrated by Y. Shi et al. inanimal models that the natural calpain inhibitor calpastatin is downregulated during renal ischemia reperfusion (Am. J. Physiol. RenalPhysiol. 2000, 279, pp. 509-517). Furthermore, A. Dnyanmote et al.,Toxicology and Applied Pharmacology 2006, 215, pp. 146-157, have shownthat inhibition of calpain via overexpression of calpastatin reduces theprogression of DCVC-induced renal injury in a model of acute renalfailure. In addition, Peltier et al. have demonstrated that calpainactivation and secretion promotes glomerular injury in experimentalglomerulonephritis (J. Am. Soc. Nephrol. 2006, 17, pp. 3415-3423). Ithas also been shown that calpain inhibitors reduce renal dysfunction andinjury caused by renal ischemia-reperfusion and thus may be useful inenhancing the tolerance of the kidney against renal injury associatedwith aortovascular surgery or renal transplantation (P. Chatterjee etal., Biochem. Pharmacol. 2005, 7, pp. 1121-1131).

Further possible applications of calpain inhibitors are detailed in: M.E. Saez et al.; Drug Discovery Today 2006, 11 (19/20), pp. 917-923; N.O. Carragher, Curr. Pharm. Design 2006, 12, pp. 615-638; K. K. Wang etal.; Drugs of the Future 1998, 23 (7), pp. 741-749; and Trends inPharmacol. Sci. 1994, 15, pp. 412-419.

With the calpain inhibitors described to date a general distinction ismade between irreversible and reversible inhibitors, and peptide andnon-peptide inhibitors.

Irreversible inhibitors are usually alkylating substances. They have thedisadvantage that they firstly react unselectively and/or are unstablein the body. Thus, corresponding inhibitors often show unwanted sideeffects such as toxicity, and application thereof is therefore markedlyrestricted. The irreversible inhibitors include for example epoxidessuch as E64, α-halo ketones, and disulfides.

A large number of known reversible calpain inhibitors are peptidealdehydes which are derived in particular from di- or tripeptides suchas, for example, Z-Val-Phe-H (MDL 28170). Derivatives and prodrugsstructurally derived from aldehydes are also described, especiallycorresponding acetals and hemiacetals (e.g. hydroxytetrahydro-furans,hydroxyoxazolindines, hydroxymorpholines and the like), but also iminesor hydrazones. However, under physiological conditions, peptidealdehydes and related compounds usually have the disadvantage that,owing to their reactivity, they are frequently unstable, are rapidlymetabolized and are prone to unspecific reactions which may likewisecause toxic effects (J. A. Fehrentz and B. Castro, Synthesis 1983, pp.676-78).

In recent years, a number of non-peptide carboxamides having a β-ketofunction in the amine moiety and inhibiting calpain have been described.Thus, WO-98/16512 describes 3-amino-2-oxo carboxylic acid derivativeswhose amino group is amidated with a 4-piperidinecarboxylic acidcompound. WO-99/17775 describes similar compounds which are amidatedwith a quinolinecarboxylic acid. WO-98/25883, WO-98/25899 andWO-99/54294 describe 3-amino-2-oxo carboxylic acid derivatives whoseamino group is amidated with a substituted benzoic acid. WO-99/61423describes 3-amino-2-oxo carboxylic acid derivatives whose amino group isamidated with an aromatic carboxylic acid carrying atetrahydroquinoline/isoquinoline and 2,3-dihydroindole/isoindoleresidue. Similar compounds in which the aromatic carboxylic acid residuecarries a heterocyloalkyl radical or (hetero)aryl radical which isoptionally connected via a linker are described in WO-99/54320,WO-99/54310, WO-99/54304 and WO-99/54305. Likewise, WO 08/080969describes nicotinamides of 3-amino-2-oxo carboxylic acid derivativesthat in position 2 of the pyridine ring are linked to a substitutedpyrazole via a nitrogen atom. WO-99/54293 describes benzamides of4-amino-3-oxo carboxylic acid derivatives. WO-03/080182 describes theuse of the aforementioned amides for the treatment of pulmonarydiseases. The nonpeptide calpain inhibitors mentioned therein also havea number of disadvantages, in particular a low or absent selectivity inrespect of related cysteine proteases, such as various cathepsins,likewise possibly leading to unwanted side effects.

SUMMARY OF THE INVENTION

The present invention is thus based on the object of providing compoundswhich inhibit, in particular selectively, calpain even at low serumconcentrations. The compounds were intended in particular to display ahigh selectivity in relation to the inhibition of calpain, i.e. inhibitother cystein proteases, e.g. cathepsin, not at all or only atsignificantly higher concentrations. Furthermore, the compounds shouldhave a sufficient cytosolic stability, in particular in human cells,such as human hepatocytes, and in consequence improved pharmacokinetics.

This object and further objects are achieved by the carboxamidecompounds of the general formula I described below, the tautomersthereof and the pharmaceutically suitable salts thereof:

in which

-   R¹ is hydrogen, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, where    the last 3 radicals mentioned may be partly or completely    halogenated and/or have 1, 2 or 3 substituents R^(1a),    -   C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, where a CH₂        group in the cycloalkyl moiety of the last two radicals        mentioned may be replaced by O, NH, or S, or two adjacent C        atoms may form a double bond, where the cycloalkyl moiety may        further have 1, 2, 3 or 4 radicals Rb,    -   aryl, hetaryl, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,        hetaryl-C₁-C₄-alkyl or hetaryl-C₂-C₆-alkenyl, where aryl and        hetaryl in the last 6 radicals mentioned may be unsubstituted or        carry 1, 2, 3 or 4 identical or different radicals R^(1c); where    -   R^(1a) is selected independently of one another from OH, SH,        COOH, CN, OCH₂COOH, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,        C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,        COOR^(a1), CONR^(a2)R^(a3), SO₂NR^(a2)R^(a3),        —NR^(a2)—SO₂—R^(a4), NR^(a2)—CO—R^(a5), SO₂—R^(a4) and        NR^(a6)R^(a7),    -   R^(1b) is selected independently of one another from OH, SH,        COOH, CN, OCH₂COOH, halogen, phenyl which optionally has 1, 2 or        3 substituents R^(1d), or C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, where the alkyl moieties in the last 3        substituents mentioned may be partly or completely halogenated        and/or have 1, 2 or 3 substituents R^(1a),        -   COOR^(b1), CONR^(b2)R^(b3), SO₂NR^(b2)R^(b3),            NR^(b2)—SO₂—R^(b4), NR^(b2)—CO—R^(b5), SO₂—R^(b4), and            NR^(b6)R^(b7),        -   in addition two R^(1b) radicals may together form a            C₁-C₄-alkylene group, or 2 R^(1b) radicals bonded to            adjacent C atoms of cycloalkyl may form together with the            carbon atoms to which they are bonded also a benzene ring,    -   R^(1c) is selected independently of one another from OH, SH,        halogen, NO₂, NH₂, CN, COOH, OCH₂COOH, C₁-C₆-alkyl,        C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-alkylthio, where        the alkyl moieties in the last 4 substituents mentioned may be        partly or completely halogenated and/or have 1, 2 or 3        substituents R^(1a),        -   C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-cycloalkyloxy, where the cycloalkyl moiety of the last            three radicals mentioned may have 1, 2, 3 or 4 R^(1b)            radicals, and where 1 or 2 CH₂-groups in the cycloalkyl            moiety may be replaced by O, NH or S,        -   aryl, hetaryl, O-aryl, O—CH₂-aryl, where the last three            radicals mentioned are unsubstituted in the aryl moiety or            may carry 1, 2, 3 or 4 radicals R^(1d), COOR^(c1),            CONR^(c2)R^(c3), SO₂NR^(c2)R^(c3), NR^(c2)—SO₂—R^(c4),            NR^(c2)—CO—R^(c5), SO₂—R^(c4), —(CH₂)_(p)—NR^(c6)R^(c7) with            p=0, 1, 2, 3, 4, 5 or 6 and O—(CH₂)_(q)—NR^(c6)R^(c7) with            q=2, 3, 4, 5 or 6; where        -   R^(a1), R^(b1) and R^(c1) are independently of one another            H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2            or 3 substituents R^(1a), or C₂-C₆-alkenyl, C₂-C₆-alkynyl,            C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,            C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄-alkyl, hetaryl or            hetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4            radicals mentioned are unsubstituted or have 1, 2 or 3            substituents R^(1d),        -   R^(a2), R^(b2) and R^(c2) are independently of one another            H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2            or 3 substituents R^(1a), or C₂-C₆-alkenyl, C₂-C₆-alkynyl,            C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,            C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄-alkyl, hetaryl or            hetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4            radicals mentioned are unsubstituted or have 1, 2 or 3            substituents R^(1d), and        -   R^(a3), R^(b3) and R^(c3) are independently of one another            H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2            or 3 substituents R^(1a), or C₂-C₆-alkenyl, C₂-C₆-alkynyl,            C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,            C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄-alkyl, hetaryl or            hetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4            radicals mentioned are unsubstituted or have 1, 2 or 3            substituents R^(1d), or            -   the two radicals R^(a2) and R^(a3), or R^(b2) and R^(b3)                or R^(c2) and R^(c3) form together with the N atom a 3                to 7-membered, optionally substituted nitrogen                heterocycle which may optionally have 1, 2 or 3 further                different or identical heteroatoms from the group of O,                N, S as ring members,        -   R^(a4), R^(b4) and R^(c4) are independently of one another            C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or            3 substituents R^(1a), or C₂-C₆-alkenyl, C₂-C₆-alkynyl,            C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,            C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄-alkyl, hetaryl or            hetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4            radicals mentioned are unsubstituted or have 1, 2 or 3            substituents R^(1d), and        -   R^(a5), R^(b5) and R^(c5) have independently of one another            one of the meanings mentioned for R^(a1), R^(b1) and R^(c1);        -   R^(a6), R^(b6) and R^(c6) are independently of one another            H, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-alkyl            which has 1, 2 or 3 substituents R^(1a), or C₂-C₆-alkenyl,            C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,            C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,            C₁-C₆-alkoxy-C₁-C₄-alkyl, CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl,            SO₂—C₁-C₆-alkyl, aryl, hetaryl, O-aryl, OCH₂-aryl,            aryl-C₁-C₄-alkyl, hetaryl-C₁-C₄-alkyl, CO-aryl, CO-hetaryl,            CO-(aryl-C₁-C₄-alkyl), CO-(hetaryl-C₁-C₄-alkyl), CO—O-aryl,            CO—O-hetaryl, CO—O-(aryl-C₁-C₄-alkyl),            CO—O-(hetaryl-C₁-C₄-alkyl), SO₂-aryl, SO₂-hetaryl,            SO₂-(aryl-C₁-C₄-alkyl) or SO₂-(hetaryl-C₁-C₄-alkyl), where            aryl and hetaryl in the last 18 radicals mentioned are            unsubstituted or have 1, 2 or 3 substituents R^(1d), and        -   R^(a7), R^(b7) and R^(c7) are independently of one another            H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2            or 3 substituents R^(1a), or C₂-C₆-alkenyl, C₂-C₆-alkynyl,            C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,            C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄-alkyl, hetaryl or            hetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4            radicals mentioned are unsubstituted or have 1, 2 or 3            substituents R^(1d), or            -   the two radicals R^(a6) and R^(a7), or R^(b6) and R^(b7)                or R^(c6) and R^(c7) form together with the N atom a 3                to 7-membered, optionally substituted nitrogen                heterocycle which may optionally have 1, 2 or 3 further                different or identical heteroatoms from the group of O,                N and S as ring members,            -   or two radicals R^(1b) or R^(1c) bonded to adjacent C                atoms form together with the C atoms to which they are                bonded a 4-, 5-, 6- or 7-membered, optionally                substituted carbocycle or an optionally substituted                heterocycle which has 1, 2 or 3 different or identical                heteroatoms from the group of O, N and S as ring                members;        -   R^(1d) is selected from halogen, OH, SH, NO₂, COOH, C(O)NH₂,            CHO, CN, NH₂, OCH₂COOH, C₁-C₆-alkyl, C₁-C₆-haloalkyl,            C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,            C₁-C₆-haloalkylthio, CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl,            NH—C₁-C₆-alkyl, NHCHO, NH—C(O)C₁-C₆-alkyl, and            SO₂—C₁-C₆-alkyl;-   R² is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, where a CH₂    group in the cycloalkyl moiety of the last two radicals mentioned    may be replaced by O, NH, or S, or two adjacent C atoms may form a    double bond, where the cycloalkyl moiety may additionally have 1, 2,    3 or 4 R^(2a) radicals;    -   aryl, O-aryl, O—CH₂-aryl, hetaryl, aryl-C₁-C₆-alkyl,        aryl-C₂-C₆-alkenyl, hetaryl-C₁-C₄-alkyl or        hetaryl-C₂-C₆-alkenyl, where aryl and hetaryl in the last 8        radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4        identical or different R^(2b) radicals; where    -   R^(2a) has one of the meanings indicated for R^(1b), and    -   R^(2b) has one of the meanings indicated for R^(1c);-   R^(3a) and R^(3b) are independently of one another hydroxy or    C₁-C₄-alkoxy, or together with the carbon atom to which they are    bonded are C═O; or-   R^(3a) and R^(3b) together form a moiety S-Alk-S, O-Alk-S or    O-Alk-O, wherein Alk is linear C₂-C₅-alkandiyl, which may be    unsubstituted or substituted with 1, 2, 3 or 4 radicals selected    from C₁-C₄-alkyl or halogen;-   X is hydrogen or a radical of the formulae C(═O)—O—R^(x1),    C(═O)—NR^(x2)R^(x3), C(═O)—N(R^(x4))—(C₁-C₆-alkylene)-NR^(x2)R^(x3)    or C(═O)—N(R^(x4))NR^(x2)R^(x3), in which    -   R^(x1) is hydrogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl        which has 1, 2 or 3 substituents R^(xa), or C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl,        heterocycloalkyl in the last 6 radicals mentioned are        unsubstituted or have 1, 2 or 3 substituents R^(xa), or aryl,        aryl-C₁-C₄-alkyl, hetaryl or hetaryl-C₁-C₄-alkyl, where aryl and        hetaryl in the last 4 radicals mentioned are unsubstituted or        have 1, 2 or 3 substituents R^(xd),    -   R^(x2) is H, OH, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl        which has 1, 2 or 3 substituents R^(xa), or C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl,        O—C₁-C₆-alkyl, where alkyl, alkoxy, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl in the last 10 radicals mentioned        are unsubstituted or have 1, 2 or 3 substituents R^(xa),        -   aryl, O-aryl, O—CH₂-aryl, hetaryl, O—CH₂-hetaryl,            aryl-C₁-C₄-alkyl, hetaryl-C₁-C₄-alkyl, CO-aryl, CO-hetaryl,            CO-(aryl-C₁-C₄-alkyl), CO-(hetaryl-C₁-C₄-alkyl), CO—O-aryl,            CO—O-hetaryl, CO—O-(aryl-C₁-C₄-alkyl),            CO—O-(hetaryl-C₁-C₄-alkyl), SO₂-aryl, SO₂-hetaryl,            SO₂-(aryl-C₁-C₄-alkyl) or SO₂-(hetaryl-C₁-C₄-alkyl), where            aryl and hetaryl in the last 19 radicals mentioned are            unsubstituted or have 1, 2 or 3 substituents R^(xd),    -   R^(x3) is H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has        1, 2 or 3 substituents R^(xa), or C₂-C₆-alkenyl, C₂-C₆-alkynyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl,        heterocycloalkyl in the last 6 radicals mentioned are        unsubstituted or have 1, 2 or 3 substituents R^(xa),        -   aryl, aryl-C₁-C₄-alkyl, hetaryl or hetaryl-C₁-C₄-alkyl,            where aryl and hetaryl in the last 4 radicals mentioned are            unsubstituted or have 1, 2 or 3 substituents R^(xd), or        -   the two radicals R^(x2) and R^(x3) form together with the N            atom a 3- to 7-membered nitrogen heterocycle which may            optionally have 1, 2 or 3 further different or identical            heteroatoms from the group of O, N, S as ring members, and            which may have 1, 2 or 3 substituents R^(xb), and    -   R^(x4) is H, OH, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl        which has 1, 2 or 3 substituents R^(xa), or C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, where alkyl,        alkenyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl in the        last 9 radicals mentioned are unsubstituted or have 1, 2 or 3        substituents R^(xa), aryl, O-aryl, O—CH₂-aryl, hetaryl,        aryl-C₁-C₄-alkyl, hetaryl-C₁-C₄-alkyl, CO-aryl, CO-hetaryl,        CO-(aryl-C₁-C₄-alkyl), CO-(hetaryl-C₁-C₄-alkyl), CO—O-aryl,        CO—O-hetaryl, CO—O-(aryl-C₁-C₄-alkyl),        CO—O-(hetaryl-C₁-C₄-alkyl), SO₂-aryl, SO₂-hetaryl,        SO₂-(aryl-C₁-C₄-alkyl) or SO₂-(hetaryl-C₁-C₄-alkyl), where aryl        and hetaryl in the last 18 radicals mentioned are unsubstituted        or have 1, 2 or 3 substituents R^(xd), and        -   where R^(xa) has one of the meanings indicated for R^(1a),            R^(xb) has one of the meanings indicated for R^(1b), and            R^(xd) has one of the meanings indicated for R^(1d);-   Y¹, Y², Y³ or Y⁴ are CR^(y), or one or two of the variables Y¹, Y²,    Y³ or Y⁴ are a nitrogen atom, and the remaining variables Y¹, Y², Y³    or Y⁴ are CR^(y);    -   R^(y) is selected independently of one another from hydrogen,        OH, SH, halogen, NO₂, NH₂, CN, CF₃, CHF₂, CH₂F, O—CF₃, O—CHF₂,        O—CH₂F, COOH, OCH₂COOH, C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-alkylthio, where the last 4        radicals mentioned may be partly or completely halogenated        and/or have 1, 2 or 3 substituents R^(ya), C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-cycloalkyl-O, where the        cycloalkyl moiety in the last three radicals mentioned may have        1, 2, 3 or 4 R^(yb) radicals, and where 1 or 2 CH₂-groups in the        cycloalkyl moiety may be replaced by O, NH or S,        -   aryl, hetaryl, O-aryl, CH₂-aryl, O—CH₂-aryl, where the last            4 radicals mentioned are unsubstituted in the aryl moiety or            may carry 1, 2, 3 or 4 radicals R^(yd),        -   COOR^(y1), CONR^(y2)R^(y3), SO₂NR^(y2)R^(y3),            —NH—SO₂—R^(y4),        -   NH—CO—R^(y5), SO₂—R^(y4),        -   —(CH₂)_(p)—NR^(y6)R^(y7) with p=0, 1, 2, 3, 4, 5 or 6 and        -   O—(CH₂)_(q)—NR^(y6)R^(y7) with q=2, 3, 4, 5 or 6;        -   or two R^(y) radicals bonded to adjacent C atoms form            together with the C atoms to which they are bonded a 4-, 5-,            6- or 7-membered, optionally substituted carbocycle or an            optionally substituted heterocycle which has 1, 2 or 3            different or identical heteroatoms from the group of O, N, S            as ring members, where        -   R^(ya) has one of the meanings indicated for R^(1a),        -   R^(yb) has one of the meanings indicated for R^(1b),        -   R^(yd) has one of the meanings indicated for R^(1d),        -   R^(y1) has one of the meanings indicated for R^(c1),        -   R^(y2) has one of the meanings indicated for R^(c2),        -   R^(y3) has one of the meanings indicated for R^(c3),        -   R^(y4) has one of the meanings indicated for R^(c4),        -   R^(y5) has one of the meanings indicated for R^(c5),        -   R^(y6) has one of the meanings indicated for R^(c6), and        -   R^(y7) has one of the meanings indicated for R^(c7);-   W is a radical of the formulae W1 or W2:

-   -   in which    -   * means the linkage to the 6-membered aromatic ring, and # means        the linkage to R²,    -   m is 0 or 1,    -   Q is O, S or NR^(ww),    -   R^(w) is selected from OH, SH, halogen, NO₂, NH₂, CN, COOH,        OCH₂COOH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,        C₁-C₆-alkylthio, where the last 4 radicals mentioned may be        partly or completely halogenated and/or have 1, 2 or 3        substituents R^(wa),        -   C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-cycloalkyloxy, where the cycloalkyl moiety of the last            three radicals mentioned may have 1, 2, 3 or 4 radicals            R^(wb),        -   aryl, O-aryl, O—CH₂-aryl, hetaryl, where the last four            radicals mentioned are unsubstituted in the aryl moiety or            may carry 1, 2, 3 or 4 radicals R^(wd),        -   COOR^(w1), CONR^(w2)R^(w3), SO₂NR^(w2)R^(w3),            NR^(w2)—SO₂—R^(w4),        -   NR^(w2)—CO—R^(w5), SO₂—R^(w4),        -   —(CH₂)_(p)—NR^(w6)R^(w7) with p=0, 1, 2, 3, 4, 5 or 6 and        -   O—(CH₂)_(q)—NR^(w6)R^(w7) with q=2, 3, 4, 5 or 6;        -   or two R^(w) radicals bonded to adjacent C atoms form            together with the C atoms to which they are bonded a 4-, 5-,            6- or 7-membered, optionally substituted carbocycle or an            optionally substituted heterocycle which has 1, 2 or 3            different or identical heteroatoms from the group of O, N, S            as ring members, where        -   R^(wa) has one of the meanings indicated for R^(1a),        -   R^(wb) has one of the meanings indicated for R^(1b),        -   R^(wd) has one of the meanings indicated for R^(1d),        -   R^(w1) has one of the meanings indicated for R^(c1),        -   R^(w2) has one of the meanings indicated for R^(c2),        -   R^(w3) has one of the meanings indicated for R^(c3),        -   R^(w4) has one of the meanings indicated for R^(c4),        -   R^(w5) has one of the meanings indicated for R^(c5),        -   R^(w6) has one of the meanings indicated for R^(c6),        -   R^(w7) has one of the meanings indicated for R^(c7),    -   R^(ww) is selected from H, OH, NH₂, CN, CF₃, CHF₂, CH₂F, O—CF₃,        O—CHF₂, O—CH₂F, COOH, OCH₂COOH, C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₁-C₆-alkoxy-C₁-C₄-alkyl, where the last 4 radicals mentioned        may be partly or completely halogenated and/or have 1, 2 or 3        substituents R^(wa),        -   C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,            C₃-C₇-cycloalkyloxy, where the cycloalkyl moiety of the last            three radicals mentioned may have 1, 2, 3 or 4 radicals            R^(wb),        -   aryl, O-aryl, O—CH₂-aryl, hetaryl, where the last four            radicals mentioned are unsubstituted in the aryl moiety or            may carry 1, 2, 3 or 4 radicals R^(wd),        -   COOR^(w1), CONR^(w2)R^(w3), SO₂NR^(w2)R^(w3),            NR^(w2)—SO₂—R^(w4),        -   NR^(w2)—CO—R^(w5), SO₂—R^(w4),        -   —(CH₂)_(p)—NR^(w6)R^(w7) with p=0, 1, 2, 3, 4, 5 or 6 and        -   O—(CH₂)_(q)—NR^(w6)R^(w7) with q=2, 3, 4, 5 or 6;

-   or

-   W forms together with R² a radical of the formula W3:

-   -   in which    -   * means the linkage to the 6-membered aromatic ring,    -   Q has one of the meanings indicated for Q in formula W1,    -   k is 0, 1 or 2, and    -   R^(w*) has one of the meanings indicated for R^(w).

The present invention therefore relates to the carboxamide compounds ofthe general formula I, their tautomers and the pharmaceutically suitablesalts of the carboxamide compounds I.

The carboxamide compounds of the invention of the formula I, their saltsand their tautomers effectively inhibit calpain even at lowconcentrations. They additionally show a high selectivity in relation tothe inhibition of the calpain compared with other cysteine proteasessuch as cathepsin B, cathepsin K, cathepsin L and cathepsin S.

The carboxamide compounds of the invention of the formula I, their saltsand their tautomers are therefore particularly suitable for treatingdisorders, impairments and conditions in creatures, especially humancreatures, which are associated with an elevated calpain activity.

The invention therefore also relates to the use of carboxamide compoundsof the formula I, their tautomers and their pharmaceutically suitablesalts for the manufacture of a medicament, in particular of a medicamentwhich is suitable for the treatment of a disorder or a condition whichis associated with an elevated calpain activity.

The invention further relates to a medicament, in particular amedicament which is suitable for the treatment of a disorder or acondition which is associated with an elevated calpain activity. Themedicament comprises at least one carboxamide compound of the formula I,as described herein, a tautomer or a pharmaceutically suitable salt ofthe compound I.

The invention further relates to a method for the therapeutic and/orprophylactic treatment of a mammal requiring a treatment, which methodcomprises administering an effective amount of at least one compound ofthe formula I as described herein, a tautomer thereof or apharmaceutically suitable salt thereof, for the treatment of adisease/disorder, of a condition or of an impairment which is associatedwith an elevated calpain activity or which is set forth in any of theclaims.

DETAILED DESCRIPTION OF THE INVENTION

The carboxamide compounds of the formula I may be in the form of β-ketocompounds, i.e. the radicals R^(3a) and R^(3b) in the compounds of theformula I form together with the carbon atom to which they are bonded acarbonyl group as shown in the formula on the left in Scheme A. Thecompounds of the invention may also be in the form of a hydrate, i.e.the radicals R^(3a) and R^(3b) are each OH, as shown in the formula onthe right in Scheme A. R¹, R², W, X and Y in Scheme A have theaforementioned meanings.

In the presence of water, especially under physiological conditions,usually both the β-keto form and the hydrate form are present in amixture.

Where only the β-keto form is indicated in the following formulae anddescriptions, this is intended to include also the hydrate and mixturesthereof with the β-keto form unless indicated otherwise. Hydrates andβ-keto forms are equally suitable as calpain inhibitors.

The carboxamide compounds of the invention of the formula I are alsoable to form tautomers when R^(3a) and R^(3b) form a carbonyl grouptogether with the carbon atom to which they are bonded. The tautomersare equally suitable as calpain inhibitors. Particular examples oftautomers to be mentioned are the compounds of the formula I-T:

R¹, R², W, X and Y in formula I-T have the aforementioned meanings.

The carboxamide compounds of the invention of the formula I can alsoform hemiacetals, hemiketals, acetals or ketals with alkanols. Thesecompounds are equally suitable as calpain inhibitors as they areprodrugs of the compounds I, where CR^(3a)R^(3b) is a carbonyl group(i.e. C═O) or C(OH)₂. Accordingly, compounds where one or both radicalsR^(3a) and R^(3b) are a radical derived from an alkanol, and especiallyC₁-C₄-alkoxy, can also be used according to the invention.

The term prodrug, as used herein refers to a compound which istransformed under metabolic conditions into a compound of the formula I.Apart from the aforementioned hemiacetals, hemiketals, acetals andketals, prodrugs of the compounds I include the compounds of the formulaI, wherein R^(3a) and R^(3b) together form a group O-Alk-O, S-Alk-O orS-Alk-S, where Alk is linear C₂-C₅-alkandiyl, which may be unsubstitutedor substituted with 1, 2, 3 or 4 radicals selected from C₁-C₄-alkyl orhalogen, examples for such groups including O(CH₂)₂O, O(CH₂)₅O,O(CH₂)₄O, S(CH₂)₂O, S(CH₂)₅O, S(CH₂)₄O, etc. Further prodrugs of thecompounds I include the compounds of the formula I, wherein R^(3a) andR^(3b) together with the carbon atom form a group C═NR³, where R³ isselected from H, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyl-C₁-C₄-alkyl, C₂-C₆-alkenyloxy,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₄-alkyloxy. Under metabolicconditions, the aforementioned prodrugs are transformed into thecorresponding β-keto compounds of the formula I (CR^(3a)R^(3b) is C═O)or into the hydrates thereof (CR^(3a)R^(3b) is C(OH)₂).

It is equally possible to use pharmaceutically suitable salts of thecarboxamide compounds of the formula I, of their tautomers or of theirprodrugs, especially acid addition salts with physiologically toleratedorganic or inorganic acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonicacids having 1 to 12 carbon atoms, e.g. C₁-C₄-alkylsulfonic acids suchas methanesulfonic acid, cycloaliphatic sulfonic acids such asS-(+)-10-camphorsulfonic acids, and aromatic sulfonic acids such asbenzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylicacids and hydroxy carboxylic acids having 2 to 10 carbon atoms, such asoxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lacticacid, tartaric acid, citric acid, glycolic acid and adipic acid, as wellas cis- and trans-cinnamic acid, furan-2-carboxylic acid and benzoicacid. Further suitable acids are described in “Fortschritte derArzneimittelforschung”, Volume 10, pages 224 et seq., Birkhäuser Verlag,Basel and Stuttgart, 1966. The physiologically tolerated salts of thecompounds of the formula I may be in the form of mono-, di-, tri- ortetrasalts, meaning that they may comprise 1, 2, 3 or 4 of theaforementioned acid molecules per molecule of the formula I. The acidmolecules may be present in their acidic form or as anion.

The compounds of the invention may be in the form of a mixture ofdiastereomers, or of a mixture of diastereomers in which one of the twodiastereomers is enriched, or of essentially diastereomerically purecompounds (diastereomeric excess de>90%). The compounds are preferablyin the form of essentially diastereomerically pure compounds(diastereomeric excess de>90%). The compounds I of the invention mayfurthermore be in the form of a mixture of enantiomers (for example asracemate), of a mixture of enantiomers in which one of the twoenantiomers is enriched, or essentially in enantiomerically purecompounds (enantiomeric excess ee>90%). However, the compounds of theinvention are frequently prone to racemization in relation to thestereochemistry of the carbon atom which carries the radical R¹, so thatmixtures are frequently obtained in relation to this carbon atom, orcompounds which exhibit a uniform stereochemistry in relation to this Catom form mixtures under physiological conditions. However, in relationto other stereocenters and the occurrence, associated therewith, ofenantiomers and diastereomers, it is preferred to employ the compoundsenantiomerically pure or diastereomerically pure.

In the context of the present description, unless stated otherwise, theterms “alkyl”, “alkoxy”, “alkylthio”, “haloalkyl”, “haloalkoxy”,“haloalkylthio”, “alkenyl”, “alkynyl”, “alkylene” and radicals derivedtherefrom always include both unbranched and branched “alkyl”, “alkoxy”,“alkylthio”, “haloalkyl”, “haloalkoxy”, “haloalkylthio”, “alkenyl”,“alkynyl” and “alkylene”, respectively.

The prefix C_(n)-C_(m)— indicates the respective number of carbons inthe hydrocarbon unit. Unless indicated otherwise, halogenatedsubstituents preferably have one to five identical or different halogenatoms, especially fluorine atoms or chlorine atoms. C₀-Alkylene or(CH₂)₀ or similar expressions in the context of the descriptiondesignate, unless indicated otherwise, a single bond.

The term “halogen” designates in each case, fluorine, bromine, chlorineor iodine, specifically fluorine, chlorine or bromine.

Examples of other meanings are:

Alkyl, and the alkyl moieties for example in alkoxy, alkylthio,arylalkyl, hetarylalkyl, cycloalkylalkyl or alkoxyalkyl: saturated,straight-chain or branched hydrocarbon radicals having one or more Catoms, e.g. 1 to 4, 1 to 6 or 1 to 10 carbon atoms, e.g. C₁-C₆-alkylsuch as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl.In one embodiment of the invention, alkyl stands for small alkyl groupssuch as C₁-C₄-alkyl. In another embodiment of the invention, alkylstands for larger alkyl groups such as C₅-C₁₀-alkyl.

Haloalkyl: an alkyl radical having ordinarily 1 to 6 or 1 to 4 C atomsas mentioned above, whose hydrogen atoms are partly or completelyreplaced by halogen atoms such as fluorine, chlorine, bromine and/oriodine, e.g. chloromethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl,2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl,2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl,3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl,1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl,1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyland nonafluorobutyl.

Cycloalkyl, and the cycloalkyl moieties for example in cycloalkoxy orcycloalkyl-C₁-C₆-alkyl: monocyclic, saturated hydrocarbon groups havingthree or more C atoms, e.g. 3 to 7 carbon ring members, for example 3,4, 5, 6 or 7 carbon ring members, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl.

Alkenyl, and alkenyl moieties for example in aryl-(C₂-C₆)-alkenyl:monounsaturated, straight-chain or branched hydrocarbon radicals havingtwo or more C atoms, e.g. 2 to 4, 2 to 6 or 2 to 10 carbon atoms and onedouble bond in any position, e.g. C₂-C₆-alkenyl such as ethenyl,1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl.

Alkynyl: straight-chain or branched hydrocarbon groups having two ormore C atoms, e.g. 2 to 4, 2 to 6 or 2 to 10 carbon atoms and one or twotriple bonds in any position but nonadjacent, e.g. C₂-C₆-alkynyl such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl,3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl.

Alkoxy or alkoxy moieties for example in alkoxyalkyl:

Alkyl as defined above having preferably 1 to 6 or 1 to 4 C atoms, whichis linked via an O atom: e.g. methoxy, ethoxy, n-propoxy,1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy,3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy,2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyor 1-ethyl-2-methylpropoxy.

Haloalkoxy: alkoxy as described above, in which the hydrogen atoms ofthese groups are partly or completely replaced by halogen atoms, i.e.for example C₁-C₆-haloalkoxy, such as chloromethoxy, dichloromethoxy,trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy,2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,2,2,2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy,3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy,3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy,2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy,1-(fluoromethyl)-2-fluoroethoxy, 1-(chloromethyl)-2-chloroethoxy,1-(bromomethyl)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy,4-bromobutoxy, nonafluorobutoxy, 5-fluoro-1-pentoxy, 5-chloro-1-pentoxy,5-bromo-1-pentoxy, 5-iodo-1-pentoxy, 5,5,5-trichloro-1-pentoxy,undecafluoropentoxy, 6-fluoro-1-hexoxy, 6-chloro-1-hexoxy,6-bromo-1-hexoxy, 6-iodo-1-hexoxy, 6,6,6-trichloro-1-hexoxy ordodecafluorohexoxy, specifically chloromethoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy or2,2,2-trifluoroethoxy.

Alkoxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in whichone hydrogen atom is replaced by an alkoxy radical ordinarily having 1to 6 or 1 to 4 C atoms. Examples thereof are CH₂—OCH₃, CH₂—OC₂H₅,n-propoxymethyl, CH₂—OCH(CH₃)₂, n-butoxymethyl, (1-methylpropoxy)methyl,(2-methylpropoxy)methyl, CH₂—OC(CH₃)₃, 2-(methoxy)ethyl,2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(1-methylethoxyl)ethyl,2-(n-butoxy)ethyl, 2-(1-methylpropoxyl)ethyl, 2-(2-methylpropoxyl)ethyl,2-(1,1-dimethylethoxyl)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl,2-(n-propoxy)propyl, 2-(1-methylethoxyl)propyl, 2-(n-butoxy)propyl,2-(1-methylpropoxyl)propyl, 2-(2-methylpropoxyl)propyl,2-(1,1-dimethylethoxyl)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl,3-(n-propoxy)propyl, 3-(1-methylethoxyl)propyl, 3-(n-butoxy)propyl,3-(1-methylpropoxyl)propyl, 3-(2-methylpropoxyl)propyl,3-(1,1-dimethylethoxyl)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,2-(n-propoxy)butyl, 2-(1-methylethoxyl)butyl, 2-(n-butoxy)butyl,2-(1-methylpropoxyl)butyl, 2-(2-methylpropoxyl)butyl,2-(1,1-dimethylethoxyl)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl,3-(n-propoxy)butyl, 3-(1-methylethoxyl)butyl, 3-(n-butoxy)butyl,3-(1-methylpropoxyl)butyl, 3-(2-methylpropoxyl)butyl,3-(1,1-dimethylethoxyl)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,4-(n-propoxy)butyl, 4-(1-methylethoxyl)butyl, 4-(n-butoxy)butyl,4-(1-methylpropoxyl)butyl, 4-(2-methylpropoxyl)butyl,4-(1,1-dimethylethoxyl)butyl, etc.

Alkylthio: alkyl as defined above preferably having 1 to 6 or 1 to 4 Catoms, which is linked via an S atom, e.g. methylthio, ethylthio,n-propylthio and the like.

Haloalkylthio: haloalkyl as defined above preferably having 1 to 6 or 1to 4 C atoms, which is linked via an S atom, e.g. fluoromethylthio,difluoromethylthio, trifluoromethylthio, 2-fluoroethylthio,2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, pentafluoroethylthio,2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio,2,3-difluoropropylthio, and heptafluoropropylthio.

Aryl: a mono-, bi- or tricyclic aromatic hydrocarbon radical such asphenyl or naphthyl, especially phenyl.

Heterocyclyl: a heterocyclic radical which may be saturated or partlyunsaturated and which ordinarily has 3, 4, 5, 6, 7 or 8 ring atoms,where ordinarily 1, 2, 3 or 4, in particular 1, 2 or 3, of the ringatoms are heteroatoms such as N, S or O, besides carbon atoms as ringmembers.

Examples of saturated heterocycles are in particular:

Heterocycloalkyl: i.e. a saturated heterocyclic radical which ordinarilyhas 3, 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ringatoms are heteroatoms such as N, S or O, besides carbon atoms as ringmembers. These include for example:

-   -   C-bonded, 3-4-membered saturated rings such as    -   2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl,        1-azetidinyl, 2-azetidinyl.    -   C-bonded, 5-membered saturated rings such as    -   tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,        tetrahydrothien-2-yl, tetrahydrothien-3-yl,        tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,        tetrahydropyrazol-3-yl, tetrahydropyrazol-4-yl,        tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,        tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl,        1,2-oxathiolan-4-yl, 1,2-oxathiolan-5-yl,        tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl,        tetrahydroisothiazol-5-yl, 1,2-dithiolan-3-yl,        1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,        tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl,        tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl,        tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,        tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,        1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,        1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl.    -   C-bonded, 6-membered saturated rings such as:    -   tetrahydropyran-2-yl, tetrahydropyran-3-yl,        tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl,        piperidin-4-yl, tetrahydrothiopyran-2-yl,        tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl,        1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl,        1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl,        1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl,        1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl,        1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl,        1,2-dithian-4-yl, hexahydropyrimidin-2-yl,        hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl,        hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,        hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,        tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,        tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,        tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,        tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,        tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,        tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,        tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,        tetrahydro-1,2-oxazin-6-yl.    -   N-bonded, 5-membered saturated rings such as:    -   tetrahydropyrrol-1-yl, tetrahydropyrazol-1-yl,        tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl,        tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl,        tetrahydrothiazol-3-yl.    -   N-bonded, 6-membered saturated rings such as:    -   piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl,        hexahydropyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl,        tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl,        tetrahydro-1,4-oxazin-4-yl, tetrahydro-1,2-oxazin-2-yl.

Unsaturated heterocyclic radicals which ordinarily have 4, 5, 6 or 7ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatomssuch as N, S or O, besides carbon atoms as ring members. These includefor example:

-   -   C-bonded, 5-membered, partially unsaturated rings such as:    -   2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl,        2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl,        4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl,        2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl,        2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl,        4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl,        2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl,        2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl,        4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl,        3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl,        3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl,        4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl,        4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl,        2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl,        4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl,        4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl,        2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl,        2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl,        2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl,        4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl,        2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl,        2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl,        2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl,        4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl,        4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl,        2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl,        2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl,        4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl,        4,5-dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl,        2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl,        2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl,        2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl,        4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol-5-yl,        2,5-dihydrothiazol-2-yl, 2,5-dihydrothiazol-4-yl,        2,5-dihydrothiazol-5-yl, 2,3-dihydrothiazol-2-yl,        2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl,        1,3-dioxol-2-yl, 1,3-dioxol-4-yl, 1,3-dithiol-2-yl,        1,3-dithiol-4-yl, 1,3-oxathiol-2-yl, 1,3-oxathiol-4-yl,        1,3-oxathiol-5-yl.    -   C-bonded, 6-membered, partially unsaturated rings such as:    -   2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,        2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,        2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,        2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,        2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,        1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,        1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-3-yl,        1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,        2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,        2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,        2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,        2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,        2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,        1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,        1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl,        2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,        2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,        2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl,        4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl,        4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl,        1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl,        2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl,        2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl,        2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl,        1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl,        1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl,        3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl,        3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl,        3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl,        2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl,        2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl,        2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl,        2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl,        2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3-yl,        2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl,        2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl,        2H-5,6-dihydro-1,2-thiazin-4-yl,        2H-5,6-dihydro-1,2-thiazin-5-yl,        2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl,        4H-5,6-dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl,        4H-5,6-dihydro-1,2-oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl,        4H-5,6-dihydro-1,2-thiazin-4-yl,        4H-5,6-dihydro-1,2-thiazin-5-yl,        4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl,        2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl,        2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro-1,2-thiazin-3-yl,        2H-3,6-dihydro-1,2-thiazin-4-yl,        2H-3,6-dihydro-1,2-thiazin-5-yl,        2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl,        2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl,        2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl,        2H-3,4-dihydro-1,2-thiazin-4-yl,        2H-3,4-dihydro-1,2-thiazin-5-yl,        2H-3,4-dihydro-1,2-thiazin-6-yl,        2,3,4,5-tetrahydropyridazin-3-yl,        2,3,4,5-tetrahydropyridazin-4-yl,        2,3,4,5-tetrahydropyridazin-5-yl,        2,3,4,5-tetrahydropyridazin-6-yl,        3,4,5,6-tetrahydropyridazin-3-yl,        3,4,5,6-tetrahydropyridazin-4-yl,        1,2,5,6-tetrahydropyridazin-3-yl,        1,2,5,6-tetrahydropyridazin-4-yl,        1,2,5,6-tetrahydropyridazin-5-yl,        1,2,5,6-tetrahydropyridazin-6-yl,        1,2,3,6-tetrahydropyridazin-3-yl,        1,2,3,6-tetrahydropyridazin-4-yl,        4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl,        4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl,        4H-5,6-dihydro-1,3-thiazin-2-yl,        4H-5,6-dihydro-1,3-thiazin-4-yl,        4H-5,6-dihydro-1,3-thiazin-5-yl,        4H-5,6-dihydro-1,3-thiazin-6-yl,        3,4,5-6-tetrahydropyrimidin-2-yl,        3,4,5,6-tetrahydropyrimidin-4-yl,        3,4,5,6-tetrahydropyrimidin-5-yl,        3,4,5,6-tetrahydropyrimidin-6-yl,        1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl,        1,2,3,4-tetrahydropyrimidin-2-yl,        1,2,3,4-tetrahydropyrimidin-4-yl,        1,2,3,4-tetrahydropyrimidin-5-yl,        1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl,        2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl,        2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl,        2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl,        2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl,        2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl,        4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl,        4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl,        6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl,        6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl,        6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl,        2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl,        2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl,        2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl,        4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,        1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,        1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,        1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,        1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,        1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,        1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,        1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,        3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or        3,4-dihydropyrimidin-6-yl.    -   N-bonded, 5-membered, partially unsaturated rings such as:    -   2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,        4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl,        2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl,        2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl,        2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl,        2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl,        2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl.    -   N-bonded, 6-membered, partially unsaturated rings such as:    -   1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,        1,4-dihydropyridin-1-yl, 1,2-dihydropyridin-1-yl,        2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl,        2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl,        2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl,        2,3,4,5-tetrahydropyridazin-2-yl,        1,2,5,6-tetrahydropyridazin-1-yl,        1,2,5,6-tetrahydropyridazin-2-yl,        1,2,3,6-tetrahydropyridazin-1-yl,        3,4,5,6-tetrahydropyrimidin-3-yl,        1,2,3,4-tetrahydropyrazin-1-yl,        1,2,3,4-tetrahydropyrimidin-1-yl,        1,2,3,4-tetrahydropyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl,        2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl, 4H-1,4-oxazin-4-yl,        4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,        1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,        1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl.

Hetaryl: a 5- or 6-membered aromatic heterocyclic radical whichordinarily has 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected fromoxygen and sulfur and, if appropriate, 1, 2 or 3 nitrogen atoms as ringmembers besides carbon atoms as ring members: for example

-   -   C-bonded, 5-membered heteroaromatic radicals having 1, 2, 3 or 4        nitrogen atoms or a heteroatom selected from oxygen and sulfur        and, if appropriate, having 1, 2 or 3 nitrogen atoms as ring        members, such as:    -   2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl,        pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl,        isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,        isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl,        oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl,        thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,        1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl,        1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl,        1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,        1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl,        1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl.    -   C-bonded, 6-membered heteroaromatic radicals having 1, 2, 3 or 4        nitrogen atoms as ring members, such as:    -   pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl,        pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,        pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,        1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl.    -   N-bonded, 5-membered heteroaromatic radicals having 1, 2, 3 or 4        nitrogen atoms as ring members, such as:    -   pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,        1,2,4-triazol-1-yl, tetrazol-1-yl.

Heterocyclyl also includes bicyclic heterocycles which have one of theaforementioned 5- or 6-membered heterocyclic rings and a furthersaturated, unsaturated or aromatic carbocycle fused thereto, for examplea benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a further5- or 6-membered heterocyclic ring fused thereto, where the latter maylikewise be saturated, unsaturated or aromatic. These include forexample quinolinyl, isoquinolinyl, indolyl, indolizynyl, isoindolyl,indazolyl, benzofuryl, benzothienyl, benzo[b]thiazolyl, benzoxazolyl,benzthiazolyl and benzimidazolyl. Examples of 5- to 6-memberedheteroaromatic compounds comprising a fused benzene ring includedihydroindolyl, dihydroindolizynyl, dihydroisoindolyl,dihydroquinolinyl, dihydroisoquinolinyl, chromenyl and chromanyl.

Arylalkyl: an aryl radical as defined above which is linked via analkylene group, in particular via a methylene, 1,1-ethylene or1,2-ethylene group, e.g. benzyl, 1-phenylethyl and 2-phenylethyl.

Arylalkenyl: an aryl radical as defined above, which is linked via analkenylene group, in particular via a 1,1-ethenyl, 1,2-ethenyl or1,3-propenyl group, e.g. 2-phenylethen-1-yl and 1-phenylethen-1-yl.

Cycloalkoxy: a cycloalkyl radical as defined above which is linked viaan oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy orcyclohexyloxy.

Cycloalkylalkyl: a cycloalkyl radical as defined above which is linkedvia an alkylene group, in particular via a methylene, 1,1-ethylene or1,2-ethylene group, e.g. cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl or cyclohexylmethyl.

Heterocyclylalkyl and hetarylalkyl: a heterocyclyl or hetaryl radical asdefined above which is linked via an alkylene group, in particular via amethylene, 1,1-ethylene or 1,2-ethylene group.

The expression “optionally substituted” means in the context of thepresent invention that the respective moiety is substituted or has 1, 2or 3, in particular 1, substituents which are selected from halogen,C₁-C₄-alkyl, OH, SH, CN, CF₃, O—CF₃, COOH, O—CH₂—COOH, C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl, CONH₂,CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂,SO₂N—(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl, NH—CO—C₁-C₆-alkyl,SO₂—C₁-C₆-alkyl, O-phenyl, O—CH₂-phenyl, CONH-phenyl, SO₂NH-phenyl,CONH-hetaryl, SO₂NH-hetaryl, SO₂-phenyl, NH—SO₂-phenyl, NH—CO-phenyl,NH—SO₂-hetaryl and NH—CO-hetaryl, where phenyl and hetaryl in the last11 radicals mentioned are unsubstituted or may have 1, 2 or 3substituents which are selected from halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

In relation to their use as calpain inhibitors, the variables R¹, R², Wand X preferably have the following meanings, where these represent,both considered on their own and in combination with one another,special embodiments of the compounds of the formula I:

-   R¹ C₁-C₁₀-alkyl, preferably C₃-C₁₀-alkyl, which may be partly or    completely halogenated and/or have 1, 2 or 3 substituents R^(1a), in    particular unsubstituted C₁-C₁₀-alkyl, specifically unsubstituted    C₃-C₁₀-alkyl,    -   C₃-C₇-cycloalkyl-C₁-C₄-alkyl, specifically        C₃-C₇-cycloalkylmethyl, 1-(C₃-C₇-cycloalkyl)ethyl or        2-(C₃-C₇-cycloalkyl)ethyl, where the cycloalkyl moiety may have        1, 2, 3 or 4 radicals R^(1b), very specifically        cyclohexylmethyl,    -   phenyl-C₁-C₄-alkyl and hetaryl-C₁-C₄-alkyl, in particular        benzyl, 1-phenylethyl, 2-phenylethyl, hetarylmethyl,        1-hetarylethyl, 2-hetarylethyl such as thienylmethyl,        pyridinylmethyl, where phenyl and hetaryl in the last radicals        mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical        or different radicals R^(1c).    -   Preferred among these are compounds of the general formula I        where R¹ is C₃-C₁₀-alkyl which is unsubstituted or may be partly        or completely halogenated and/or have 1, 2 or 3 substituents        R^(1a), in particular C₃-C₁₀-alkyl and most preferred        C₃-C₈-alkyl.    -   Likewise preferred among these are compounds of the general        formula I where R¹ is phenyl-C₁-C₄-alkyl or hetaryl-C₁-C₄-alkyl,        where phenyl and hetaryl in the last 2 radicals mentioned is        unsubstituted or carries 1, 2, 3 or 4 identical or different        radicals R^(1c). In hetaryl-C₁-C₄-alkyl, the hetaryl moiety is        preferably pyridyl or thienyl.    -   In a particular preferred embodiment R¹ is phenyl-C₁-C₄-alkyl        and most preferred benzyl, wherein the phenyl ring in        phenyl-C₁-C₄-alkyl or benzyl is unsubstituted or carries 1, 2, 3        or 4 identical or different radicals R^(1c).    -   In this connection, R^(1a), R^(1b) and R^(1c) where present have        the aforementioned meanings. In particular:    -   R^(1a) is C₁-C₄-alkoxy or C₁-C₄-haloalkoxy;    -   R^(1b) is halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy or        C₁-C₄-haloalkoxy; and    -   R^(1c) is halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, OH, SH, CN,        COOH, O—CH₂—COOH, C₁-C₆-alkoxy, C₁-C₄-haloalkoxy,        C₁-C₆-alkylthio, C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl, CONH₂,        CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂,        SO₂N—(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl, NH—CO—C₁-C₆-alkyl,        SO₂—C₁-C₆-alkyl,        -   O-phenyl, O—CH₂-phenyl, CONH-phenyl, SO₂NH-phenyl,            CONH-hetaryl, SO₂NH-hetaryl, SO₂-phenyl, NH—SO₂-phenyl,            NH—CO-phenyl, NH—SO₂-hetaryl, NH—CO-hetaryl where phenyl and            hetaryl in the last 11 radicals mentioned are unsubstituted            or may have 1, 2 or 3 substituents which are selected from            halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and            C₁-C₄-haloalkoxy,        -   —(CH₂)_(p)—NR^(c6)R^(c7) with p=0, 1, 2, 3, 4, 5 or 6, in            particular 0, and        -   —O—(CH₂)_(q)—NR^(c6)R^(c7) with q=2, 3, 4, 5 or 6, in            particular 2, where        -   R^(c6), R^(c7) are independently of one another hydrogen or            C₁-C₆-alkyl, or together with the nitrogen atom to which            they are bonded, are a morpholine, piperidine, pyrrolidine,            azetidine or piperazine residue, where the last 5 radicals            mentioned are unsubstituted or may carry 1, 2, 3 or 4            radicals selected from C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy or C₁-C₄-haloalkoxy. R^(1c) is in particular            halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, especially            C₁-C₂-fluoroalkyl such as CF₃, CHF₂, CH₂F, specially CF₃,            C₁-C₄-alkoxy or C₁-C₄-haloalkoxy, especially            C₁-C₂-fluoroalkoxy such as O—CF₃, O—CHF₂ or O—CH₂F,            specially O—CF₃.-   R² is, in particular:    -   aryl or hetaryl, where aryl and hetaryl in the last 2 radicals        mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical        or different radicals R^(2b),    -   aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl or hetaryl-C₁-C₄-alkyl,        where aryl and hetaryl in the last 3 radicals mentioned may be        unsubstituted or carry 1, 2, 3 or 4 identical or different        radicals R^(2b).    -   Preferred among these are those compounds of the general formula        I in which R² is selected from aryl and hetaryl, specifically        from phenyl, naphthyl, thienyl and pyridyl, and most preferred        from phenyl and naphthyl, where aryl and hetaryl (or phenyl,        naphthyl, thienyl and pyridyl) may be unsubstituted or carry 1,        2, 3 or 4, in particular 1 or 2, identical or different radicals        R^(2b).    -   In this connection R^(2b) where present has the aforementioned        meanings. In particular:    -   R^(2b) is halogen, C₁-C₄-alkyl, OH, SH, CN, CF₃, O—CF₃, COOH,        O—CH₂—COOH, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₃-C₇-cycloalkyl,        COO—C₁-C₆-alkyl, CONH₂, CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl,        CON—(C₁-C₆-alkyl)₂, SO₂N—(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl,        NH—CO—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, O-phenyl, O—CH₂-phenyl,        CONH-phenyl, SO₂NH-phenyl, CONH-hetaryl, SO₂NH-hetaryl,        SO₂-phenyl, NH—SO₂-phenyl, NH—CO-phenyl, NH—SO₂-hetaryl,        NH—CO-hetaryl, where phenyl and hetaryl in the last 11 radicals        mentioned are unsubstituted or may have 1, 2 or 3 substituents        which are selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,        -   —(CH₂)_(p)—NR^(c6)R^(c7) with p=0, 1, 2, 3, 4, 5 or 6, in            particular 0, and        -   —O—(CH₂)_(q)—NR^(c6)R^(c7) with q=2, 3, 4, 5 or 6, in            particular 2, where        -   R^(c6), R^(c7) are independently of one another hydrogen or            C₁-C₆-alkyl, or together with the nitrogen atom to which            they are bonded are a morpholine, piperidine, pyrrolidine,            azetidine or piperazine residue, where the last 5 radicals            mentioned are unsubstituted or may carry 1, 2, 3 or 4            radicals selected from C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy or C₁-C₄-haloalkoxy.-   R^(3a), R^(3b) in particular OH or the group CR^(3a)R^(3b) is a    carbonyl group, wherein the latter is most preferred.-   W a radical of the formulae W1 or W2, wherein m is 0 or 1, in    particular 0, or the group W—R² is a radical of the formula W3,    wherein k is 0 or 1, in particular 0.    -   Where m or k is 1 or 2, R^(w) and R^(w*) are preferably selected        from halogen, C₁-C₆-alkyl, C₁-C₆-alkyl which is substituted by        1, 2 or 3 substituents R^(wa), or OH, SH, CN, COOH, O—CH₂—COOH,        C₁-C₆-haloalkyl, especially C₁-C₂-fluoroalkyl such as CF₃, CHF₂,        CH₂F, specially CF₃, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy especially        C₁-C₂-fluoroalkoxy such as O—CF₃, O—CHF₂ or O—CH₂F, specially        O—CF₃, C₁-C₆-alkylthio, C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl,        CONH₂, CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂,        SO₂N—(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl, NH—CO—C₁-C₆-alkyl,        SO₂—C₁-C₆-alkyl, O-phenyl, O—CH₂-phenyl, CONH-phenyl,        SO₂NH-phenyl, CONH-hetaryl, SO₂NH-hetaryl, SO₂-phenyl,        NH—SO₂-phenyl, NH—CO-phenyl, NH—SO₂-hetaryl, NH—CO-hetaryl,        where phenyl and hetaryl in the last 11 radicals mentioned are        unsubstituted or may have 1, 2 or 3 substituents which are        selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy and C₁-C₄-haloalkoxy. R^(w) and R^(w*) are in        particular selected from OH, F, Cl, CN, CF₃, C₁-C₆-alkyl which        is unsubstituted or may have 1, 2 or 3 substituents R^(wa),        C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy and        C₃-C₇-cycloalkyl. In this connection, R^(wa) has the        aforementioned meanings and is in particular C₁-C₄-alkoxy or        C₁-C₄-haloalkoxy. R^(w) and R^(w*) are particularly preferably        selected from F, Cl, CN, CF₃, CH₃, C₂H₅ and OCH₃.    -   Compounds of the formula I which are particularly preferred        among the compounds of the invention of the general formula I        are those in which W is a radical W1 or W2, wherein in each case        Q is selected from S, O and NH, specifically from S and O, and        particularly preferred among these are those in which m is 0 or        1 and specifically 0. Particular preference is given to        compounds of the formula I, wherein W is W1 or W2 and Q is S.    -   Compounds of the formula I which are particularly preferred        among the compounds of the invention of the general formula I        are those in which W—R² is a radical W3, wherein Q is selected        from S, O and NH, specifically from S and O, and particularly        preferred among these are those in which m is 0 or 1 and        specifically 0. Particular preference is given to compounds of        the formula I, wherein W—R² is a radical W3, wherein Q is S.-   X is a radical C(═O)—NR^(x2)R^(x3) in which R^(x2) and R^(x3) have    one of the aforementioned meanings. Compounds preferred among these    are those in which:    -   R^(x2) is H, OH, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl        which has 1, 2 or 3 substituents R^(xa), or C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        aryl, hetaryl, aryl-C₁-C₄-alkyl or hetaryl-C₁-C₄-alkyl, where        aryl and hetaryl in the last 4 radicals mentioned are        unsubstituted or have 1, 2 or 3 substituents R^(xd). In        particular, R^(x2) is hydrogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₁-C₆-alkyl which has 1 or 2 substituents R^(xa),        C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, aryl, hetaryl,        aryl-C₁-C₄-alkyl or hetaryl-C₁-C₄-alkyl. R^(x2) is very        particularly preferably hydrogen.    -   R^(x3) is H, C₁-C₆-alkyl, C₁-C₆-haloalkyl or C₁-C₆-alkyl which        has 1, 2 or 3 substituents R^(xa). In particular, R^(x3) is        hydrogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1        or 2 substituents R^(xa). R^(x3) is very particularly preferably        hydrogen.    -   Compounds of the formula I which are likewise preferred are        those in which the group NR^(x2)R^(x3) is a nitrogen heterocycle        of the following formulae:

-   -   in which R^(x5) is hydrogen or has the meaning indicated for        R^(xb). In particular, R^(x5) is C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₁-C₆-alkyl which has 1, 2 or 3 substituents R^(xa) or        C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        aryl-C₁-C₄-alkyl or hetaryl-C₁-C₄-alkyl, where aryl and hetaryl        in the last 2 radicals mentioned are unsubstituted or have 1, 2        or 3 substituents R^(xd), or COO—C₁-C₆-alkyl, CONH₂,        CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂,        SO₂N—(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl, CONH-phenyl,        SO₂NH-phenyl, CONH-hetaryl, SO₂NH-hetaryl, where phenyl and        hetaryl in the last 4 radicals mentioned are unsubstituted or        may have 1, 2 or 3 substituents which are selected from the        halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and        C₁-C₄-haloalkoxy. In particular, R^(x5) is hydrogen or        C₁-C₄-alkyl.    -   In a particularly preferred embodiment of the invention, X is        C(O)—NH₂.    -   In another particularly preferred embodiment of the invention, X        is C(O)—NHR^(x2a), wherein R^(x2a) has one of the meanings given        above for R^(x2), except for hydrogen. In this particular        embodiment, R^(x2a) is preferably selected from OH, C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3 substituents        R^(xa), or C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        O—C₁-C₆-alkyl, where alkyl, alkoxy, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl in the last 7 radicals mentioned        are unsubstituted or have 1, 2 or 3 substituents R^(xa), aryl,        O-aryl, O—CH₂-aryl, hetaryl, O—CH₂-hetaryl, aryl-C₁-C₄-alkyl and        hetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 7        radicals mentioned are unsubstituted or have 1, 2 or 3        substituents R^(xd). Especially, R^(x2a) is selected from        C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkylmethyl, C₁-C₆-alkoxy-C₁-C₄-alkyl and        O—C₁-C₆-alkyl.    -   In another embodiment of the invention, X is hydrogen.    -   In another embodiment of the invention, X is C(O)OR^(x1) in        which R^(x1) has the aforementioned meanings. In particular,        R^(x1) is C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1,        2 or 3 substituents R^(xa), or C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₄-alkyl,        C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,        aryl, hetaryl, aryl-C₁-C₄-alkyl or hetaryl-C₁-C₄-alkyl, where        aryl and hetaryl in the last 4 radicals mentioned are        unsubstituted or have 1, 2 or 3 substituents R^(xd).    -   In this connection, R^(xa) has the aforementioned meanings and        is in particular C₁-C₄-alkoxy or C₁-C₄-haloalkoxy. In this        connection, R^(xd) has the aforementioned meanings and is        preferably F, Cl, OH, COOH, C(O)NH₂, CN, NH₂, OCH₂COOH,        C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, CO—C₁-C₄-alkyl,        CO—O—C₁-C₄-alkyl, NH—C₁-C₄-alkyl, NH—C(O)C₁-C₄-alkyl or        SO₂—C₁-C₄-alkyl.

-   Y¹, Y², Y³ or Y⁴ are CR^(y), or one or two of the variables Y¹ to Y⁴    are a nitrogen atom and the remaining variables Y¹, Y², Y³ or Y⁴ are    CR^(y), wherein the radicals R^(y) may be identical or different,    each having one of the aforementioned meanings.    -   In a preferred embodiment of the invention, Y⁴ is N.    -   In a particular preferred embodiment of the invention, Y⁴ is N,        and Y¹, Y² and Y³ are CR^(y). Thus, in this embodiment the        divalent, 6-membered heteroaromatic radical of formula I that        includes the variables Y¹ to Y⁴ is pyridinediyl.    -   In another particular preferred embodiment of the invention, Y⁴        and Y¹ are N, and Y² and Y³ are CR^(y). Thus, in this embodiment        the divalent, 6-membered heteroaromatic radical of formula I        that includes the variables Y¹ to Y⁴ is pyrazinediyl.    -   In another particular preferred embodiment of the invention, Y⁴        and Y² are N, and Y¹ and Y³ are CR^(y). Thus, in this embodiment        the divalent, 6-membered heteroaromatic radical of formula I        that includes the variables Y¹ to Y⁴ is pyrimidinediyl.    -   In yet another particular preferred embodiment of the invention,        Y¹, Y², Y³ and Y⁴ are CR^(y). Thus, in this embodiment the        divalent, 6-membered aromatic radical of formula I that includes        the variables Y¹ to Y⁴ is benzdiyl.    -   The 6-membered (hetero)aromatic radical of formula I that        includes the variables Y¹ to Y⁴ preferably has 0, 1 or 2        identical or different substituents R^(y) other than hydrogen        and more preferably 0 or 1 substituent R^(y) other than        hydrogen. Particularly preferred are compounds of formula I,        wherein all substituents R^(y) are hydrogen.    -   Where a substituent R^(y) is present that is not hydrogen, it is        preferably selected from OH, F, Cl, NH₂, CN, CF₃, CHF₂, O—CF₃,        O—CHF₂, O—CH₂F, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₆-alkylamino,        C₁-C₆-dialkylamino, pyrrolidinyl, piperidinyl, morpholinyl,        imidazolyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,        CONR^(y2)R^(y3), SO₂NR^(y2)R^(y3), NH—SO₂—R^(y4),        —(CH₂)_(p)—NR^(y6)R^(y7), NH—CO—R^(y5), in which p is 0, 1, 2,        3, 4, or 5, and in which R^(y2), R^(y3), R^(y4), R^(y5), R^(y6),        R^(y7) have the aforementioned meanings, preferably the meanings        mentioned as preferred below, and are in particular H and        C₁-C₆-alkyl,    -   phenyl, benzyl and O-benzyl, where the phenyl ring in the last 3        groups mentioned may have 1, 2 or 3 substituents selected from        halogen, OH, SH, NO₂, COOH, C(O)NH₂, CHO, CN, NH₂, OCH₂COOH,        C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,        C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, CO—C₁-C₆-alkyl,        CO—O—C₁-C₆-alkyl, NH—C₁-C₆-alkyl, NHCHO, NH—C(O)C₁-C₆-alkyl, and        SO₂—C₁-C₆-alkyl.    -   In particular, R^(y) that is not hydrogen, is OH, F, Cl, NH₂,        CN, CF₃, CHF₂, O—CF₃, O—CHF₂, O—CH₂F, C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₁-C₆-alkylamino, C₁-C₆-dialkylamino,        pyrrolidinyl, piperidinyl, morpholinyl, imidazolyl,        C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, CONH—C₁-C₆-alkyl,        SO₂N(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl, NH—CO—C₁-C₆-alkyl,        (CH₂)_(p)—N(C₁-C₆-alkyl)₂, in which p is 2, 3 or 4.    -   R^(y) that is not hydrogen, is particularly preferably F, Cl,        CN, CF₃, CHF₂, O—CF₃, O—CHF₂, O—CH₂F or C₁-C₃-alkyl.

More preferred are compounds of the formula I wherein:

W is W1, wherein Q is O, S or NH,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W1, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W1, wherein Q is O, S or NH,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W1, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Also more preferred are compounds of the formula I wherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Otherwise, the radicals R^(x4), R^(ya), R^(wa), R^(yb), R^(wb), R^(yd),R^(wd), R^(a1), R^(b1), R^(c1), R^(y1), R^(w1), R^(a2), R^(b2), R^(c2),R^(y2), R^(w2), R^(a3), R^(b3), R^(c3), R^(y3), R^(w3), R^(a4), R^(b4),R^(c4), R^(y4), R^(w4), R^(a5), R^(b5), R^(c5), R^(y5), R^(w5), R^(a6),R^(b6), R^(c6), R^(y6), R^(w6), R^(a7), R^(b7), R^(c7), R^(y7), R^(w7)and R^(ww) have, unless otherwise indicated, independently of oneanother preferably one of the following meanings:

R^(x4): hydrogen or C₁-C₆-alkyl.R^(ya), R^(wa) independently of one another: C₁-C₄-alkoxy orC₁-C₄-haloalkoxy.R^(yb), R^(wb) independently of one another: halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy.R^(yd), R^(wd) independently of one another: F, Cl, OH, COOH, C(O)NH₂,CN, NH₂, OCH₂COOH, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, CO—C₁-C₄-alkyl,CO—O—C₁-C₄-alkyl, NH—C₁-C₄-alkyl, NH—C(O)C₁-C₄-alkyl or SO₂—C₁-C₄-alkyl.R^(a1), R^(b1), R^(c1), R^(y1), R^(w1) independently of one another:hydrogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, phenyl, benzyl, hetaryl andhetarylmethyl, where phenyl and hetaryl in the last 4 radicals mentionedare unsubstituted or have 1, 2 or 3 substituents which are selected fromhalogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy.R^(a2), R^(b2), R^(c2), R^(y2), R^(w2) independently of one another:hydrogen, C₁-C₆-alkyl, phenyl, benzyl, hetaryl and hetarylmethyl, wherephenyl and hetaryl in the last 4 radicals mentioned are unsubstituted orhave 1, 2 or 3 substituents which are selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.R^(a3), R^(b3), R^(c3), R^(y3), R^(w3) independently of one another:hydrogen or C₁-C₆-alkyl,or R^(a2) with R^(a3) (and likewise R^(b2) with R^(b3), R^(c2) withR^(c3), R^(y2) with R^(y3) and R^(w2) with R^(w3)) together with thenitrogen atom to which they are bonded are a morpholine, piperidine,pyrrolidine, azetidine or piperazine residue, where the last 5 radicalsmentioned are unsubstituted or may carry 1, 2, 3 or 4 radicals selectedfrom C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy.R^(a4), R^(b4), R^(c4), R^(y4), R^(w4) independently of one another:hydrogen, C₁-C₆-alkyl, phenyl, benzyl, hetaryl and hetarylmethyl, wherephenyl and hetaryl in the last 4 radicals mentioned are unsubstituted orhave 1, 2 or 3 substituents which are selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.R^(a5), R^(b5), R^(c5), R^(y5), R^(w5) independently of one another:hydrogen, C₁-C₆-alkyl, phenyl, benzyl, hetaryl and hetarylmethyl, wherephenyl and hetaryl in the last 4 radicals mentioned are unsubstituted orhave 1, 2 or 3 substituents which are selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.R^(a6), R^(b6), R^(c6), R^(y6), R^(w6) independently of one another:hydrogen, C₁-C₆-alkyl, phenyl, benzyl, hetaryl and hetarylmethyl, wherephenyl and hetaryl in the last 4 radicals mentioned are unsubstituted orhave 1, 2 or 3 substituents which are selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.R^(a7), R^(b7), R^(c7), R^(y7), R^(w7) independently of one another:hydrogen or C₁-C₆-alkyl,or R^(a6) with R^(a7) (and likewise R^(b6) with R^(b7), R^(c6) withR^(c7), R^(y6) with R^(y7) and R^(w6) with R^(w7)) together with thenitrogen atom to which they are bonded are a morpholine, piperidine,pyrrolidine, azetidine or piperazine residue, where the last 5 radicalsmentioned are unsubstituted or may carry 1, 2, 3 or 4 radicals selectedfrom C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy,R^(ww): hydrogen or C₁-C₄-alkyl.

Preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-A,

in which m, X, Q, Y¹, Y², Y³, Y⁴, R¹, R², R^(3a), R^(3b) and R^(w) havethe aforementioned meanings, in particular the meanings mentioned aspreferred. In formula I-A m is preferably 0 or 1 and particularly 0. Thevariable Q is preferably a sulfur atom, a oxygen atom or a NH-moiety.Preferably, the variable Y⁴ is a nitrogen atom and the remainingvariables Y¹, Y² and Y³ are each a CH-moiety, or the variables Y¹ and Y⁴or Y² and Y⁴ are each a nitrogen atom and the remaining variables Y² andY³ or Y¹ and Y³ are each a CH-moiety, or all variables Y¹, Y², Y³ and Y⁴are each a CH-moiety. Also preferred are the tautomers of I-A, thepharmaceutically suitable salts thereof and the tautomers thereof.

Also preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-B,

in which m, X, Q, Y¹, Y², Y³, Y⁴, R¹, R², R^(3a), R^(3b) and R^(w) havethe aforementioned meanings, in particular the meanings mentioned aspreferred. In formula I-B m is preferably 0 or 1 and particularly 0. Thevariable Q is preferably a sulfur atom, a oxygen atom or a NH-moiety.Preferably, the variable Y⁴ is a nitrogen atom and the remainingvariables Y¹, Y² and Y³ are each a CH-moiety, or the variables Y¹ and Y⁴or Y² and Y⁴ are each a nitrogen atom and the remaining variables Y² andY³ or Y¹ and Y³ are each a CH-moiety, or all variables Y¹, Y², Y³ and Y⁴are each a CH-moiety. Also preferred are the tautomers of I-B, thepharmaceutically suitable salts thereof and the tautomers thereof.

Also preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-C,

in which m, X, Q, Y¹, Y², Y³, Y⁴, R¹, R^(3a), R^(3b) and R^(w) have theaforementioned meanings, in particular the meanings mentioned aspreferred. In formula I-C m is preferably 0 or 1 and particularly 0. Thevariable Q is preferably a sulfur atom, a oxygen atom or a NH-moiety.Preferably, the variable Y⁴ is a nitrogen atom and the remainingvariables Y¹, Y² and Y³ are each a CH-moiety, or the variables Y¹ and Y⁴or Y² and Y⁴ are each a nitrogen atom and the remaining variables Y² andY³ or Y¹ and Y³ are each a CH-moiety, or all variables Y¹, Y², Y³ and Y⁴are each a CH-moiety. Also preferred are the tautomers of I-C, thepharmaceutically suitable salts thereof and the tautomers thereof.

Also preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-a,

in which X, W, R¹, R², R^(3a), R^(3b), have the aforementioned meanings.R^(yy) has one of the meanings indicated for R^(y) that are differentfrom hydrogen, in particular the meanings mentioned as preferred. Thevariable n is preferably 0 or 1 and particularly 0. W is preferablyselected from W1 or W2, wherein in each case Q is preferably selectedfrom S, O and NH, or W together with R² forms a radical W3, wherein Q ispreferably selected from S, O and NH. Also preferred are the tautomersof I-a, the pharmaceutically suitable salts thereof and the tautomersthereof.

Also preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-b,

in which X, W, R¹, R², R^(3a), R^(3b), have the aforementioned meanings.R^(yy) has one of the meanings indicated for R^(y) that are differentfrom hydrogen, in particular the meanings mentioned as preferred. Thevariable n is preferably 0 or 1 and particularly 0. W is preferablyselected from W1 or W2, wherein in each case Q is preferably selectedfrom S, O and NH, or W together with R² forms a radical W3, wherein Q ispreferably selected from S, O and NH. Also preferred are the tautomersof I-b, the pharmaceutically suitable salts thereof and the tautomersthereof.

Also preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-c,

in which X, W, R¹, R², R^(3a), R^(3b), have the aforementioned meanings.R^(yy) has one of the meanings indicated for R^(y) that are differentfrom hydrogen, in particular the meanings mentioned as preferred. Thevariable n is preferably 0 or 1 and particularly 0. W is preferablyselected from W1 or W2, wherein in each case Q is preferably selectedfrom S, O and NH, or W together with R² forms a radical W3, wherein Q ispreferably selected from S, O and NH. Also preferred are the tautomersof I-c, the pharmaceutically suitable salts thereof and the tautomersthereof.

Also preferred among the carboxamide compounds of the invention of theformula I are those compounds which correspond to the general formulaI-d,

in which X, W, R¹, R², R^(3a), R^(3b), have the aforementioned meanings.R^(yy) has one of the meanings indicated for R^(y) that are differentfrom hydrogen, in particular the meanings mentioned as preferred. Thevariable n is preferably 0 or 1 and particularly 0. W is preferablyselected from W1 or W2, wherein in each case Q is preferably selectedfrom S, O and NH, or W together with R² forms a radical W3, wherein Q ispreferably selected from S, O and NH. Also preferred are the tautomersof 1-d, the pharmaceutically suitable salts thereof and the tautomersthereof.

Particularly preferred are compounds of the formulae I-a and I-bwherein:

W is W1, wherein Q is O, S or NH,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W1, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,

X is CONH₂, and

R^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W1, wherein Q is O, S or NH,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W1, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W is W2, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Likewise articularly preferred are compounds of the formulae I-a and I-bwherein:

W—R² is W3, wherein Q is O, S or NH, in particular O or S,R¹ is C₃-C₈-alkyl,X is CONHR^(x2a), wherein R^(x2a) are as defined above andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

In turn preferred among the carboxamide compounds of the invention ofthe formula I-A are compounds which correspond to the general formulaeI-A.a, I-A.b, I-A.c or I-A.d,

in which n, R^(yy), m, R^(w), Q, X, R¹, R², R^(3a) and R^(3b) have theaforementioned meanings, in particular those mentioned as preferred.

Particularly preferred are compounds of the formulae I-A.a and I-A.bwherein:

m is 0;R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONH₂ or CONHR^(x2a), wherein R^(x2a) are as defined above, andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Particularly preferred are compounds of the formulae I-A.a and I-A.bwherein:

m is 0;R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONH₂ or CONHR^(x2a), wherein R^(x2a) are as defined above, andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Preferred examples of compounds of formula I-A.a and I-A.b comprise

-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-{4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyl-1,3-thiazol-2-yl)pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]pyridine-3-carboxamide,-   N-(1-amino-1,2-dioxoheptan-3-yl)-2-(4-phenyl-1,3-thiazol-2-yl)nicotinamide,-   N-(1-amino-1,2-dioxoheptan-3-yl)-2-(4-phenyl-1,3-thiazol-2-yl)benzamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyl-1,3-thiazol-2-yl)benzamide,-   N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyl-1,3-thiazol-2-yl)nicotinamide,-   N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenylthiazol-2-yl)nicotinamide    and-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyloxazol-2-yl)nicotinamide,    and    the pharmaceutically suitable salts thereof, their prodrugs, their    hydrates and the tautomers thereof.

In turn preferred among the carboxamide compounds of the invention ofthe formula I-B are compounds which correspond to the general formulaeI-B.a, I-B.b, I-B.c or I-B.d,

in which n, R^(y), m, R^(w), Q, X, R¹, R², R^(3a) and R^(3b) have theaforementioned meanings, in particular those mentioned as preferred.

Particularly preferred are compounds of the formulae I-B.a and I-B.bwherein:

m is 0;R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONH₂ or CONHR^(x2a), wherein R^(x2a) are as defined above, andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Particularly preferred are compounds of the formulae I-B.a and I-B.bwherein:

m is 0;R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONH₂ or CONHR^(x2a), wherein R^(x2a) are as defined above, andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Preferred examples of compounds of formula I-B.a and I-B.b comprise

-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-{2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyl-1,3-thiazol-4-yl)pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(2-chlorophenyl)-1,3-thiazol-4-yl]pyridine-3-carboxamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(naphthalen-2-yl)-1,3-thiazol-4-yl]pyridine-3-carboxamide,-   N-(1-amino-1,2-dioxoheptan-3-yl)-2-(2-phenylthiazol-4-yl)nicotinamide,-   N-(1-amino-1,2-dioxoheptan-3-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide,-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide,-   N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide,-   N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide    and-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyloxazol-4-yl)nicotinamide    and    the pharmaceutically suitable salts, their prodrugs, their hydrates    and the tautomers thereof.

In turn preferred among the carboxamide compounds of the invention ofthe formula I-C are compounds which correspond to the general formulaeI-C.a, I-C.b, I-C.c or I-C.d,

in which n, R^(yy), m, R^(W), Q, X, R¹, R^(3a) and R^(3b) have theaforementioned meanings, in particular those mentioned as preferred.

Particularly preferred are compounds of the formulae I-C.a and I-C.bwherein:

m is 0;R¹ is phenyl-C₁-C₄-alkyl, which is unsubstituted or carries 1, 2, 3 or 4identical or different radicals R^(1c),R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONH₂ or CONHR^(x2a), wherein R^(x2a) are as defined above, andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Particularly preferred are compounds of the formulae I-C.a and I-C.bwherein:

m is 0;R¹ is C₃-C₈-alkyl,R² is phenyl or is naphthyl, where phenyl and naphthyl may beunsubstituted or substituted with 1 or 2 identical or different radicalsR^(2b),X is CONH₂ or CONHR^(x2a), wherein R^(x2a) are as defined above, andR^(3a) and R^(3b) are each OH or the group CR^(3a)R^(3b) is a carbonylgroup.

Preferred examples of compounds of formula I-C.a comprise:

-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1H-benzimidazol-2-yl)pyridine-3-carboxamide;-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide;    and-   N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1,3-benzo[d]oxazol-2-yl)pyridine-3-carboxamide    and    the pharmaceutically suitable salts thereof, their prodrugs, their    hydrates and the tautomers thereof.

The compounds of the general formulae I-a, I-b, I-c and I-d, which areindicated in Tables 1 to 160 below and in which CR^(3a)R^(3b) is acarbonyl function or a C(OH)₂ group, and their tautomers, prodrugs andpharmaceutically acceptable salts, represent per se preferredembodiments of the present invention. The meanings for R¹ and R²indicated in Table A below, as well as the meanings for R¹ and W3(represented by W—R²) indicated in Table B below, represent embodimentsof the invention which are likewise preferred independently of oneanother and especially in combination.

In subsequent Tables 1 to 80 the variables W1a, W1b, W2a and W2b havethe following meanings:

in which * and # have the have the aforementioned meanings.

Table 1

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 2

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-F, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 3

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 4

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CN, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 5

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 6

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 7

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 8

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 9

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 10

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 11

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 12

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-F, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 13

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 14

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CN, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 15

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 16

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 17

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 18

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 19

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 20

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 21

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 22

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-F, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 23

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 24

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CN, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 25

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 26

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 27

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 28

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 29

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 30

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 31

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, n=0, i.e. (R^(y))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 32

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 33

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 34

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CN, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 35

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 36

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 37

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(y))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 38

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 39

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 40

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 41

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 42

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-F, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 43

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 44

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CN, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 45

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 46

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 47

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 48

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 49

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 50

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 51

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 52

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-F, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 53

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 54

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CN, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 55

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 56

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 57

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 58

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 59

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 60

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 61

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 62

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-F, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 63

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 64

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CN, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 65

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 66

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 67

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 68

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 69

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 70

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 71

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 72

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-F, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 73

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-Cl, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 74

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CN, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 75

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 76

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 77

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 78

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 79

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 80

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 81

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 82

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W is W1a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 83

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 84

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 85

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 86

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 87

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 88

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 89

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 90

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 91

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 92

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W is W1b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 93

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 94

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 95

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 96

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 97

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(y))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 98

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 99

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 100

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 101

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 102

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W is W2a,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 103

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 104

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 105

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 106

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 107

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 108

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 109

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 110

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 111

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 112

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W is W2b,and the combination of R¹ and R² for a compound in each case correspondsto one line of Table A.

Table 113

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 114

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 115

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 116

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 117

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 118

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 119

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 120

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 121

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n) isabsent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A (here and below -c-C₃H₅ iscyclopropyl).

Table 122

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 123

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 124

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 125

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, W isW1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 126

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n)is absent, W is W1a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 127

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, Wis W1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 128

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, Wis W1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 129

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, Wis W1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 130

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, Wis W1a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 131

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n) isabsent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 132

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 133

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 134

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 135

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 136

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n)is absent, W is W1b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 137

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(y))_(n) is 5-F, W isW1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 138

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, Wis W1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 139

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, Wis W1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 140

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, Wis W1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 141

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n) isabsent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 142

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 143

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 144

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 145

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, W isW2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 146

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n)is absent, W is W2a, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 147

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, Wis W2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 148

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, Wis W2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 149

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, Wis W2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 150

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, Wis W2a, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 151

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n) isabsent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 152

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 153

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 154

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 155

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, W isW2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 156

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n)is absent, W is W2b, and the combination of R¹ and R² for a compound ineach case corresponds to one line of Table A.

Table 157

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, Wis W1b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 158

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, Wis W2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 159

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, Wis W2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

Table 160

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, Wis W2b, and the combination of R¹ and R² for a compound in each casecorresponds to one line of Table A.

TABLE A No. R¹ R² A-1 n-Butyl Phenyl A-2 n-Butyl 2-Methylphenyl A-3n-Butyl 2-Methoxyphenyl A-4 n-Butyl 2-Chlorophenyl A-5 n-Butyl2-Fluorophenyl A-6 n-Butyl 2-Trifluoromethylphenyl A-7 n-Butyl3-Methylphenyl A-8 n-Butyl 3-Methoxyphenyl A-9 n-Butyl 3-ChlorophenylA-10 n-Butyl 3-Fluorophenyl A-11 n-Butyl 3-[(Phenylmethyl)oxy]phenylA-12 n-Butyl 3-Morpholin-4-ylphenyl A-13 n-Butyl3-(Morpholin-4-ylmethyl)phenyl A-14 n-Butyl 3-Pyrrolidin-1-ylphenyl A-15n-Butyl 4-Methylphenyl A-16 n-Butyl 4-(1-Methylethyl)phenyl A-17 n-Butyl4-Methoxyphenyl A-18 n-Butyl 4-Chlorophenyl A-19 n-Butyl 4-FluorophenylA-20 n-Butyl 4-Trifluoromethylphenyl A-21 n-Butyl 4-DiethylaminophenylA-22 n-Butyl 4-[(Diethylamino)methyl]phenyl A-23 n-Butyl 4-CyanophenylA-24 n-Butyl 4-(Piperidin-1-yl)phenyl A-25 n-Butyl4-(4-Methylpiperazin-1-yl)phenyl A-26 n-Butyl 4-Pyrrolidin-1-ylphenylA-27 n-Butyl 4-(1H-Imidazol-1-yl)phenyl A-28 n-Butyl4-Morpholin-4-ylphenyl A-29 n-Butyl 4-(Morpholin-4-ylmethyl)phenyl A-30n-Butyl 2,4-Difluorophenyl A-31 n-Butyl 2,6-Difluorophenyl A-32 n-Butyl3,5-Difluorophenyl A-33 n-Butyl 2,4-Dichlorophenyl A-34 n-Butyl2,6-Dichlorophenyl A-35 n-Butyl 3,5-Dichlorophenyl A-36 n-Butyl2-Chloro-4-fluorophenyl A-37 n-Butyl 2-Chloro-4-morpholin-4-ylphenylA-38 n-Butyl 2-Fluoro-4-morpholin-4-ylphenyl A-39 n-Butyl Pyridin-2-ylA-40 n-Butyl Pyridin-4-yl A-41 n-Butyl Thien-2-yl A-42 n-Butyl2,3-Dihydrobenzo[b]furan-5-yl A-43 Isobutyl Phenyl A-44 Isobutyl2-Methylphenyl A-45 Isobutyl 2-Methoxyphenyl A-46 Isobutyl2-Chlorophenyl A-47 Isobutyl 2-Fluorophenyl A-48 Isobutyl2-Trifluoromethylphenyl A-49 Isobutyl 3-Methylphenyl A-50 Isobutyl3-Methoxyphenyl A-51 Isobutyl 3-Chlorophenyl A-52 Isobutyl3-Fluorophenyl A-53 Isobutyl 3-[(Phenylmethyl)oxy]phenyl A-54 Isobutyl3-Morpholin-4-ylphenyl A-55 Isobutyl 3-(Morpholin-4-ylmethyl)phenyl A-56Isobutyl 3-Pyrrolidin-1-ylphenyl A-57 Isobutyl 4-Methylphenyl A-58Isobutyl 4-(1-Methylethyl)phenyl A-59 Isobutyl 4-Methoxyphenyl A-60Isobutyl 4-Chlorophenyl A-61 Isobutyl 4-Fluorophenyl A-62 Isobutyl4-Trifluoromethylphenyl A-63 Isobutyl 4-Diethylaminophenyl A-64 Isobutyl4-[(Diethylamino)methyl]phenyl A-65 Isobutyl 4-Cyanophenyl A-66 Isobutyl4-(Piperidin-1-yl)phenyl A-67 Isobutyl 4-(4-Methylpiperazin-1-yl)phenylA-68 Isobutyl 4-Pyrrolidin-1-ylphenyl A-69 Isobutyl4-(1H-Imidazol-1-yl)phenyl A-70 Isobutyl 4-Morpholin-4-ylphenyl A-71Isobutyl 4-(Morpholin-4-ylmethyl)phenyl A-72 Isobutyl 2,4-DifluorophenylA-73 Isobutyl 2,6-Difluorophenyl A-74 Isobutyl 3,5-Difluorophenyl A-75Isobutyl 2,4-Dichlorophenyl A-76 Isobutyl 2,6-Dichlorophenyl A-77Isobutyl 3,5-Dichlorophenyl A-78 Isobutyl 2-Chloro-4-fluorophenyl A-79Isobutyl 2-Chloro-4-morpholin-4-ylphenyl A-80 Isobutyl2-Fluoro-4-morpholin-4-ylphenyl A-81 Isobutyl Pyridin-2-yl A-82 IsobutylPyridin-4-yl A-83 Isobutyl Thien-2-yl A-84 Isobutyl2,3-Dihydrobenzo[b]furan-5-yl A-85 Benzyl Phenyl A-86 Benzyl2-Methylphenyl A-87 Benzyl 2-Methoxyphenyl A-88 Benzyl 2-ChlorophenylA-89 Benzyl 2-Fluorophenyl A-90 Benzyl 2-Trifluoromethylphenyl A-91Benzyl 3-Methylphenyl A-92 Benzyl 3-Methoxyphenyl A-93 Benzyl3-Chlorophenyl A-94 Benzyl 3-Fluorophenyl A-95 Benzyl3-[(Phenylmethyl)oxy]phenyl A-96 Benzyl 3-Morpholin-4-ylphenyl A-97Benzyl 3-(Morpholin-4-ylmethyl)phenyl A-98 Benzyl3-Pyrrolidin-1-ylphenyl A-99 Benzyl 4-Methylphenyl A-100 Benzyl4-(1-Methylethyl)phenyl A-101 Benzyl 4-Methoxyphenyl A-102 Benzyl4-Chlorophenyl A-103 Benzyl 4-Fluorophenyl A-104 Benzyl4-Trifluoromethylphenyl A-105 Benzyl 4-Diethylaminophenyl A-106 Benzyl4-[(Diethylamino)methyl]phenyl A-107 Benzyl 4-Cyanophenyl A-108 Benzyl4-(Piperidin-1-yl)phenyl A-109 Benzyl 4-(4-Methylpiperazin-1-yl)phenylA-110 Benzyl 4-Pyrrolidin-1-ylphenyl A-111 Benzyl4-(1H-Imidazol-1-yl)phenyl A-112 Benzyl 4-Morpholin-4-ylphenyl A-113Benzyl 4-(Morpholin-4-ylmethyl)phenyl A-114 Benzyl 2,4-DifluorophenylA-115 Benzyl 2,6-Difluorophenyl A-116 Benzyl 3,5-Difluorophenyl A-117Benzyl 2,4-Dichlorophenyl A-118 Benzyl 2,6-Dichlorophenyl A-119 Benzyl3,5-Dichlorophenyl A-120 Benzyl 2-Chloro-4-fluorophenyl A-121 Benzyl2-Chloro-4-morpholin-4-ylphenyl A-122 Benzyl2-Fluoro-4-morpholin-4-ylphenyl A-123 Benzyl Pyridin-2-yl A-124 BenzylPyridin-4-yl A-125 Benzyl Thien-2-yl A-126 Benzyl2,3-Dihydrobenzo[b]furan-5-yl A-127 4-Chlorobenzyl Phenyl A-1284-Chlorobenzyl 2-Methylphenyl A-129 4-Chlorobenzyl 2-Methoxyphenyl A-1304-Chlorobenzyl 2-Chlorophenyl A-131 4-Chlorobenzyl 2-Fluorophenyl A-1324-Chlorobenzyl 2-Trifluoromethylphenyl A-133 4-Chlorobenzyl3-Methylphenyl A-134 4-Chlorobenzyl 3-Methoxyphenyl A-135 4-Chlorobenzyl3-Chlorophenyl A-136 4-Chlorobenzyl 3-Fluorophenyl A-137 4-Chlorobenzyl3-[(Phenylmethyl)oxy]phenyl A-138 4-Chlorobenzyl 3-Morpholin-4-ylphenylA-139 4-Chlorobenzyl 3-(Morpholin-4-ylmethyl)phenyl A-140 4-Chlorobenzyl3-Pyrrolidin-1-ylphenyl A-141 4-Chlorobenzyl 4-Methylphenyl A-1424-Chlorobenzyl 4-(1-Methylethyl)phenyl A-143 4-Chlorobenzyl4-Methoxyphenyl A-144 4-Chlorobenzyl 4-Chlorophenyl A-145 4-Chlorobenzyl4-Fluorophenyl A-146 4-Chlorobenzyl 4-Trifluoromethylphenyl A-1474-Chlorobenzyl 4-Diethylaminophenyl A-148 4-Chlorobenzyl4-[(Diethylamino)methyl]phenyl A-149 4-Chlorobenzyl 4-Cyanophenyl A-1504-Chlorobenzyl 4-(Piperidin-1-yl)phenyl A-151 4-Chlorobenzyl4-(4-Methylpiperazin-1-yl)phenyl A-152 4-Chlorobenzyl4-Pyrrolidin-1-ylphenyl A-153 4-Chlorobenzyl 4-(1H-Imidazol-1-yl)phenylA-154 4-Chlorobenzyl 4-Morpholin-4-ylphenyl A-155 4-Chlorobenzyl4-(Morpholin-4-ylmethyl)phenyl A-156 4-Chlorobenzyl 2,4-DifluorophenylA-157 4-Chlorobenzyl 2,6-Difluorophenyl A-158 4-Chlorobenzyl3,5-Difluorophenyl A-159 4-Chlorobenzyl 2,4-Dichlorophenyl A-1604-Chlorobenzyl 2,6-Dichlorophenyl A-161 4-Chlorobenzyl3,5-Dichlorophenyl A-162 4-Chlorobenzyl 2-Chloro-4-fluorophenyl A-1634-Chlorobenzyl 2-Chloro-4-morpholin-4-ylphenyl A-164 4-Chlorobenzyl2-Fluoro-4-morpholin-4-ylphenyl A-165 4-Chlorobenzyl Pyridin-2-yl A-1664-Chlorobenzyl Pyridin-4-yl A-167 4-Chlorobenzyl Thien-2-yl A-1684-Chlorobenzyl 2,3-Dihydrobenzo[b]furan-5-yl A-169 4-MethoxybenzylPhenyl A-170 4-Methoxybenzyl 2-Methylphenyl A-171 4-Methoxybenzyl2-Methoxyphenyl A-172 4-Methoxybenzyl 2-Chlorophenyl A-1734-Methoxybenzyl 2-Fluorophenyl A-174 4-Methoxybenzyl2-Trifluoromethylphenyl A-175 4-Methoxybenzyl 3-Methylphenyl A-1764-Methoxybenzyl 3-Methoxyphenyl A-177 4-Methoxybenzyl 3-ChlorophenylA-178 4-Methoxybenzyl 3-Fluorophenyl A-179 4-Methoxybenzyl3-[(Phenylmethyl)oxy]phenyl A-180 4-Methoxybenzyl 3-Morpholin-4-ylphenylA-181 4-Methoxybenzyl 3-(Morpholin-4-ylmethyl)phenyl A-1824-Methoxybenzyl 3-Pyrrolidin-1-ylphenyl A-183 4-Methoxybenzyl4-Methylphenyl A-184 4-Methoxybenzyl 4-(1-Methylethyl)phenyl A-1854-Methoxybenzyl 4-Methoxyphenyl A-186 4-Methoxybenzyl 4-ChlorophenylA-187 4-Methoxybenzyl 4-Fluorophenyl A-188 4-Methoxybenzyl4-Trifluoromethylphenyl A-189 4-Methoxybenzyl 4-Diethylaminophenyl A-1904-Methoxybenzyl 4-[(Diethylamino)methyl]phenyl A-191 4-Methoxybenzyl4-Cyanophenyl A-192 4-Methoxybenzyl 4-(Piperidin-1-yl)phenyl A-1934-Methoxybenzyl 4-(4-Methylpiperazin-1-yl)phenyl A-194 4-Methoxybenzyl4-Pyrrolidin-1-ylphenyl A-195 4-Methoxybenzyl 4-(1H-Imidazol-1-yl)phenylA-196 4-Methoxybenzyl 4-Morpholin-4-ylphenyl A-197 4-Methoxybenzyl4-(Morpholin-4-ylmethyl)phenyl A-198 4-Methoxybenzyl 2,4-DifluorophenylA-199 4-Methoxybenzyl 2,6-Difluorophenyl A-200 4-Methoxybenzyl3,5-Difluorophenyl A-201 4-Methoxybenzyl 2,4-Dichlorophenyl A-2024-Methoxybenzyl 2,6-Dichlorophenyl A-203 4-Methoxybenzyl3,5-Dichlorophenyl A-204 4-Methoxybenzyl 2-Chloro-4-fluorophenyl A-2054-Methoxybenzyl 2-Chloro-4-morpholin-4-ylphenyl A-206 4-Methoxybenzyl2-Fluoro-4-morpholin-4-ylphenyl A-207 4-Methoxybenzyl Pyridin-2-yl A-2084-Methoxybenzyl Pyridin-4-yl A-209 4-Methoxybenzyl Thien-2-yl A-2104-Methoxybenzyl 2,3-Dihydrobenzo[b]furan-5-yl A-211 CyclohexylmethylPhenyl A-212 Cyclohexylmethyl 2-Methylphenyl A-213 Cyclohexylmethyl2-Methoxyphenyl A-214 Cyclohexylmethyl 2-Chlorophenyl A-215Cyclohexylmethyl 2-Fluorophenyl A-216 Cyclohexylmethyl2-Trifluoromethylphenyl A-217 Cyclohexylmethyl 3-Methylphenyl A-218Cyclohexylmethyl 3-Methoxyphenyl A-219 Cyclohexylmethyl 3-ChlorophenylA-220 Cyclohexylmethyl 3-Fluorophenyl A-221 Cyclohexylmethyl3-[(Phenylmethyl)oxy]phenyl A-222 Cyclohexylmethyl3-Morpholin-4-ylphenyl A-223 Cyclohexylmethyl3-(Morpholin-4-ylmethyl)phenyl A-224 Cyclohexylmethyl3-Pyrrolidin-1-ylphenyl A-225 Cyclohexylmethyl 4-Methylphenyl A-226Cyclohexylmethyl 4-(1-Methylethyl)phenyl A-227 Cyclohexylmethyl4-Methoxyphenyl A-228 Cyclohexylmethyl 4-Chlorophenyl A-229Cyclohexylmethyl 4-Fluorophenyl A-230 Cyclohexylmethyl4-Trifluoromethylphenyl A-231 Cyclohexylmethyl 4-DiethylaminophenylA-232 Cyclohexylmethyl 4-[(Diethylamino)methyl]phenyl A-233Cyclohexylmethyl 4-Cyanophenyl A-234 Cyclohexylmethyl4-(Piperidin-1-yl)phenyl A-235 Cyclohexylmethyl4-(4-Methylpiperazin-1-yl)phenyl A-236 Cyclohexylmethyl4-Pyrrolidin-1-ylphenyl A-237 Cyclohexylmethyl4-(1H-Imidazol-1-yl)phenyl A-238 Cyclohexylmethyl 4-Morpholin-4-ylphenylA-239 Cyclohexylmethyl 4-(Morpholin-4-ylmethyl)phenyl A-240Cyclohexylmethyl 2,4-Difluorophenyl A-241 Cyclohexylmethyl2,6-Difluorophenyl A-242 Cyclohexylmethyl 3,5-Difluorophenyl A-243Cyclohexylmethyl 2,4-Dichlorophenyl A-244 Cyclohexylmethyl2,6-Dichlorophenyl A-245 Cyclohexylmethyl 3,5-Dichlorophenyl A-246Cyclohexylmethyl 2-Chloro-4-fluorophenyl A-247 Cyclohexylmethyl2-Chloro-4-morpholin-4-ylphenyl A-248 Cyclohexylmethyl2-Fluoro-4-morpholin-4-ylphenyl A-249 Cyclohexylmethyl Pyridin-2-ylA-250 Cyclohexylmethyl Pyridin-4-yl A-251 Cyclohexylmethyl Thien-2-ylA-252 Cyclohexylmethyl 2,3-Dihydrobenzo[b]furan-5-yl A-2532-Thienylmethyl Phenyl A-254 2-Thienylmethyl 2-Methylphenyl A-2552-Thienylmethyl 2-Methoxyphenyl A-256 2-Thienylmethyl 2-ChlorophenylA-257 2-Thienylmethyl 2-Fluorophenyl A-258 2-Thienylmethyl2-Trifluoromethylphenyl A-259 2-Thienylmethyl 3-Methylphenyl A-2602-Thienylmethyl 3-Methoxyphenyl A-261 2-Thienylmethyl 3-ChlorophenylA-262 2-Thienylmethyl 3-Fluorophenyl A-263 2-Thienylmethyl3-[(Phenylmethyl)oxy]phenyl A-264 2-Thienylmethyl 3-Morpholin-4-ylphenylA-265 2-Thienylmethyl 3-(Morpholin-4-ylmethyl)phenyl A-2662-Thienylmethyl 3-Pyrrolidin-1-ylphenyl A-267 2-Thienylmethyl4-Methylphenyl A-268 2-Thienylmethyl 4-(1-Methylethyl)phenyl A-2692-Thienylmethyl 4-Methoxyphenyl A-270 2-Thienylmethyl 4-ChlorophenylA-271 2-Thienylmethyl 4-Fluorophenyl A-272 2-Thienylmethyl4-Trifluoromethylphenyl A-273 2-Thienylmethyl 4-Diethylaminophenyl A-2742-Thienylmethyl 4-[(Diethylamino)methyl]phenyl A-275 2-Thienylmethyl4-Cyanophenyl A-276 2-Thienylmethyl 4-(Piperidin-1-yl)phenyl A-2772-Thienylmethyl 4-(4-Methylpiperazin-1-yl)phenyl A-278 2-Thienylmethyl4-Pyrrolidin-1-ylphenyl A-279 2-Thienylmethyl 4-(1H-Imidazol-1-yl)phenylA-280 2-Thienylmethyl 4-Morpholin-4-ylphenyl A-281 2-Thienylmethyl4-(Morpholin-4-ylmethyl)phenyl A-282 2-Thienylmethyl 2,4-DifluorophenylA-283 2-Thienylmethyl 2,6-Difluorophenyl A-284 2-Thienylmethyl3,5-Difluorophenyl A-285 2-Thienylmethyl 2,4-Dichlorophenyl A-2862-Thienylmethyl 2,6-Dichlorophenyl A-287 2-Thienylmethyl3,5-Dichlorophenyl A-288 2-Thienylmethyl 2-Chloro-4-fluorophenyl A-2892-Thienylmethyl 2-Chloro-4-morpholin-4-ylphenyl A-290 2-Thienylmethyl2-Fluoro-4-morpholin-4-ylphenyl A-291 2-Thienylmethyl Pyridin-2-yl A-2922-Thienylmethyl Pyridin-4-yl A-293 2-Thienylmethyl Thien-2-yl A-2942-Thienylmethyl 2,3-Dihydrobenzo[b]furan-5-yl A-295 Pyridin-3-ylmethylPhenyl A-296 Pyridin-3-ylmethyl 2-Methylphenyl A-297 Pyridin-3-ylmethyl2-Methoxyphenyl A-298 Pyridin-3-ylmethyl 2-Chlorophenyl A-299Pyridin-3-ylmethyl 2-Fluorophenyl A-300 Pyridin-3-ylmethyl2-Trifluoromethylphenyl A-301 Pyridin-3-ylmethyl 3-Methylphenyl A-302Pyridin-3-ylmethyl 3-Methoxyphenyl A-303 Pyridin-3-ylmethyl3-Chlorophenyl A-304 Pyridin-3-ylmethyl 3-Fluorophenyl A-305Pyridin-3-ylmethyl 3-[(Phenylmethyl)oxy]phenyl A-306 Pyridin-3-ylmethyl3-Morpholin-4-ylphenyl A-307 Pyridin-3-ylmethyl3-(Morpholin-4-ylmethyl)phenyl A-308 Pyridin-3-ylmethyl3-Pyrrolidin-1-ylphenyl A-309 Pyridin-3-ylmethyl 4-Methylphenyl A-310Pyridin-3-ylmethyl 4-(1-Methylethyl)phenyl A-311 Pyridin-3-ylmethyl4-Methoxyphenyl A-312 Pyridin-3-ylmethyl 4-Chlorophenyl A-313Pyridin-3-ylmethyl 4-Fluorophenyl A-314 Pyridin-3-ylmethyl4-Trifluoromethylphenyl A-315 Pyridin-3-ylmethyl 4-DiethylaminophenylA-316 Pyridin-3-ylmethyl 4-[(Diethylamino)methyl]phenyl A-317Pyridin-3-ylmethyl 4-Cyanophenyl A-318 Pyridin-3-ylmethyl4-(Piperidin-1-yl)phenyl A-319 Pyridin-3-ylmethyl4-(4-Methylpiperazin-1-yl)phenyl A-320 Pyridin-3-ylmethyl4-Pyrrolidin-1-ylphenyl A-321 Pyridin-3-ylmethyl4-(1H-Imidazol-1-yl)phenyl A-322 Pyridin-3-ylmethyl4-Morpholin-4-ylphenyl A-323 Pyridin-3-ylmethyl4-(Morpholin-4-ylmethyl)phenyl A-324 Pyridin-3-ylmethyl2,4-Difluorophenyl A-325 Pyridin-3-ylmethyl 2,6-Difluorophenyl A-326Pyridin-3-ylmethyl 3,5-Difluorophenyl A-327 Pyridin-3-ylmethyl2,4-Dichlorophenyl A-328 Pyridin-3-ylmethyl 2,6-Dichlorophenyl A-329Pyridin-3-ylmethyl 3,5-Dichlorophenyl A-330 Pyridin-3-ylmethyl2-Chloro-4-fluorophenyl A-331 Pyridin-3-ylmethyl2-Chloro-4-morpholin-4-ylphenyl A-332 Pyridin-3-ylmethyl2-Fluoro-4-morpholin-4-ylphenyl A-333 Pyridin-3-ylmethyl Pyridin-2-ylA-334 Pyridin-3-ylmethyl Pyridin-4-yl A-335 Pyridin-3-ylmethylThien-2-yl A-336 Pyridin-3-ylmethyl 2,3-Dihydrobenzo[b]furan-5-yl

With regard to subsequent Tables 161 to 200 the groups W—R² in formulaeI-a, I-b, I-c and I-d represent a radical W3, in accordance to theaforementioned definition.

Table 161

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 162

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-F, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 163

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-Cl, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 164

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CN, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 165

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 166

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 167

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 168

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 169

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 170

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 171

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 172

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-F, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 173

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-Cl, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 174

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CN, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 175

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is carbamoyl, (R^(yy))_(n) is 5-CH₃, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 176

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 177

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-F, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 178

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-Cl, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 179

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CN, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 180

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHCH₃, (R^(yy))_(n) is 5-CH₃, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 181

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 182

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 183

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 184

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 185

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, and thecombination of R¹ and W3 for a compound in each case corresponds to oneline of Table B.

Table 186

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 187

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-F, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 188

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-Cl, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 189

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CN, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 190

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NHOCH₃, (R^(yy))_(n) is 5-CH₃, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 191

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n) isabsent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 192

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 193

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 194

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 195

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C═O, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 196

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, n=0, i.e. (R^(yy))_(n)is absent, and the combination of R¹ and W3 for a compound in each casecorresponds to one line of Table B.

Table 197

Compounds of the formulae I-a, I-b, I-c and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-F, andthe combination of R¹ and W3 for a compound in each case corresponds toone line of Table B.

Table 198

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-Cl,and the combination of R¹ and W3 for a compound in each case correspondsto one line of Table B.

Table 199

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CN,and the combination of R¹ and W3 for a compound in each case correspondsto one line of Table B.

Table 200

Compounds of the formulae I-a, I-b and I-d in which the groupC(R^(3a)R^(3b)) is C(OH)₂, X is —C(O)NH-c-C₃H₅, (R^(yy))_(n) is 5-CH₃,and the combination of R¹ and W3 for a compound in each case correspondsto one line of Table B.

TABLE B No. R¹ W3 B-1 n-Butyl 1H-Benzo[d]imidozol-2-yl B-2 n-ButylBenzo[d]thiazol-2-yl B-3 n-Butyl Benzo[d]oxazol-2-yl B-4 Isobutyl1H-Benzo[d]imidozol-2-yl B-5 Isobutyl Benzo[d]thiazol-2-yl B-6 IsobutylBenzo[d]oxazol-2-yl B-7 Benzyl 1H-Benzo[d]imidozol-2-yl B-8 BenzylBenzo[d]thiazol-2-yl B-9 Benzyl Benzo[d]oxazol-2-yl B-10 4-Chlorobenzyl1H-Benzo[d]imidozol-2-yl B-11 4-Chlorobenzyl Benzo[d]thiazol-2-yl B-124-Chlorobenzyl Benzo[d]oxazol-2-yl B-13 4-Methoxybenzyl1H-Benzo[d]imidozol-2-yl B-14 4-Methoxybenzyl Benzo[d]thiazol-2-yl B-154-Methoxybenzyl Benzo[d]oxazol-2-yl B-16 Cyclohexylmethyl1H-Benzo[d]imidozol-2-yl B-17 Cyclohexylmethyl Benzo[d]thiazol-2-yl B-18Cyclohexylmethyl Benzo[d]oxazol-2-yl B-19 2-Thienylmethyl1H-Benzo[d]imidozol-2-yl B-20 2-Thienylmethyl Benzo[d]thiazol-2-yl B-212-Thienylmethyl Benzo[d]oxazol-2-yl B-22 Pyridin-3-ylmethyl1H-Benzo[d]imidozol-2-yl B-23 Pyridin-3-ylmethyl Benzo[d]thiazol-2-ylB-24 Pyridin-3-ylmethyl Benzo[d]oxazol-2-yl

The compounds of the invention of the general formula I and the requiredstarting materials used to prepare them can be prepared in analogy toknown processes of organic chemistry as are described in standard worksof organic chemistry, e.g. Houben-Weyl, “Methoden der OrganischenChemie”, Thieme-Verlag Stuttgart; Jerry March “Advanced OrganicChemistry”, 5^(th) edition, Wiley & Sons and the literature citedtherein; and R. Larock, “Comprehensive Organic Transformations”, 2^(nd)edition, Weinheim 1999, and the literature cited therein. The compoundsof the invention of the general formula I are advantageously prepared bythe methods described below and/or in the experimental section.

In the following the variables R¹, R², W, and X exhibit theaforementioned meanings and the variable Y represents the diradical:

in which n, R^(y), Y², Y³ and Y⁴ are as defined herein and wherein *indicates the point of attachment to W, while # indicates the point ofattachment to the carbonyl group.

The synthesis of C-disubstituted hetaryl residues of the formula Y usedas intermediates for preparation of compounds of the general formula Ican be achieved as described in the standard works of heterocyclicchemistry, eg. J. Joule et al. “Heterocyclic Chemistry”, Blackwell; andT. Eicher, S. Hauptmann “The Chemistry of Heterocycles”, Wiley-VCH,1^(st) edition.

The compounds of formula I can be prepared in analogy to the schemes andmethods described in WO 99/54305 and WO 2008/080969.

As shown in Scheme 1, in a first step i) a carboxylic acid II isconverted by reaction with an amino alcohol III into a correspondinghydroxy amide IV. In this connection, conventional peptide couplingmethods are ordinarily used, as are described for example in R. C.Larock, Comprehensive Organic Transformations, VCH Publisher, 1989,pages 972-976, or in Houben-Weyl, Methoden der organischen Chemie,4^(th) edition, E5, Chap. V. It may be advantageous firstly to activatethe carboxylic acid II. For this purpose, for example, the carboxylicacid II is reacted with a carbodiimide such as dicyclohexylcarbodiimide(DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in thepresence of hydroxybenzotriazole (HOBt), nitrophenol, pentafluorophenol,2,4,5-trichlorophenol or N-hydroxysuccinimide, to obtain an activatedester IIa. It may further be advantageous to prepare the activated esterIIa in the presence of a base, for example a tertiary amine. Theactivated ester IIa is subsequently reacted with the amino alcohol ofthe formula III or its hydrohalide salt to give the hydroxy amide IV.The reaction normally takes place in anhydrous inert solvents, such aschlorinated hydrocarbons, e.g. dichloromethane or dichloroethane,ethers, e.g. tetrahydrofuran or 1,4-dioxane or carboxamides, e.g.N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.Step i) is ordinarily carried out at temperatures in the range from −20°C. to +25° C.

Subsequently, in a second step ii), the hydroxy amide compound IV isoxidized to the carboxamide compound I. Various conventional oxidationreactions are suitable for this (see R. C. Larock, Comprehensive OrganicTransformations, VCH Publisher, 1989, page 604 et seq.) such as, forexample, Swern oxidation and Swern analogous oxidations (T. T. Tidwell,Synthesis 1990, pp. 857-870) or Pfitzner-Moffatt oxidation. Suitableoxidizing agents are dimethyl sulfoxide (DMSO) in combination withdicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dimethyl sulfoxide incombination with the pyridine-SO₃ complex or dimethyl sulfoxide incombination with oxalyl chloride, sodium hypochloride/TEMPO (S. L.Harbenson et al., J. Med: Chem. 1994, 37, 2918-2929), and hypervalentiodine reagents like 2-iodoxybenzoic acid (IBX) (J. Org. Chem. 1995, 60,7272), the Dess-Martin reagent (J. Org. Chem. 1983, 48, 4155) orpolymer-supported IBX (H. S Jang, Tetrahedron Lett. 2007, 48,3731-3734). Depending on the oxidizing agent used, the oxidation of thehydroxy amide compound IV takes place at temperatures of from −50 to+25° C.

Compounds of the formula IV in which X is—C(O)N(R^(x4))—(C₁-C₆-alkylene)-NR^(x2)R^(x3) or is—C(O)N(R^(x4))NR^(x2)R^(x3), in which R^(x2), R^(x3) and R^(x4) have theaforementioned meanings, can additionally be prepared by reactingcompounds of the formula III, in which X is COOH, with hydrazinecompounds of the formula NH(R^(x4))NR^(x2)R^(x3) or diamines of theformula NH(R^(x4))(C₁-C₆-alkylene)-NR^(x2)R^(x3). The reaction can thenbe carried out in analogy to step i) in Scheme 1.

The amino alcohols III can be obtained by purchase or can be prepared byprocesses disclosed in the literature (for amino hydroxy carboxylic acidderivatives, see, for example, S. L. Harbenson et al., J. Med. Chem.1994, 37, 2918-2929 or J. P. Burkhardt et al., Tetrahedron Lett. 1988,29, 3433-3436) or by the methods and procedures described in WO2008/08969.

The carboxylic acid II can be prepared by hydrolyzing the carboxylicester V with acids or bases under generally customary conditions. Thehydrolysis preferably takes place with bases such as alkali metal oralkaline earth metal hydroxides, for example lithium hydroxide, sodiumhydroxide or potassium hydroxide in aqueous medium or in a mixture ofwater and organic solvents, e.g. alcohols such as methanol or ethanol,ethers such as tetrahydrofuran or dioxane, at room temperature orelevated temperature such as 25-100° C.

In formulae II and V, R², W and Y have the aforementioned meanings. Informula V, R′ is alkyl, preferably C₁-C₆-alkyl.

In general carboxylic ester of the formula V can be prepared eitherusing Suzuki or Stille reaction employing the appropriate startingmaterials as depicted in Scheme 3.

In Scheme 3, LG represents a group like halogen or triflate, which isknown to be displaceable in metal-catalyzed reactions like Suzuki orStille. The variable V represents the complementary group required forthese reactions, like boronic acid or boronic ester in the case ofSuzuki coupling, or organo stannyl compounds for the Stille reaction.

Suzuki coupling of appropriate phenyl or hetaryl boronic acids andboronic esters, respectively, is described e.g. 1) for thiazoles in T.Bach et al., Synlett 2002, 12, 2089-2091; Tetrahedron Lett. 2000, 41,11, 1707-1710; WO 2003/2977 and WO 2005/19161; 2) for imidazoles in US2003/220372 and WO 2003/93252; 3) for oxazoles in H. Araki et al.,Synlett 2006, 4, 555-558; E. Flegau et al., Organic Letters 2006, 8, 12,2495-2498. Stille coupling of appropriate stannyl organyls withhalogenated phenyl- or hetaryl residues can be applied as described 1)for thiazoles in M. Wentland et al., J. Med. Chem. 1993, 36, 11,1580-1596; J. Haemmerle et al., Synlett 2007, 19, 2975-2978, and 2) foroxazoles in Kelly et al., Tetrahedron Lett. 1995, 36, 30, 5319-5322.

Alternatively compounds of the general formula V can be prepared bydirectly assembling the hetaryl residue W starting from appropriateprecursors as outlined below.

In cases where W represents a radical W1 or W2 with Q=S or where W—R²represents a radical W3 with Q=S the appropriate starting materials ofthe formulae VII or IX can either be purchased or prepared by methodsalready mentioned. A general overview for the synthesis of substitutedthiazoles can be found in e.g. G. Vernin, in: “Chemistry of HeterocyclicCompounds” 1979, 34, 165-335; Houben-Weyl, “Methoden der OrganischenChemie”, Vol. E8, Hetarenes III Part 2, Thieme-Verlag Stuttgart; or J.V. Metzger, in: “Comprehensive Heterocyclic Chemistry” A. R. Katritzky,C. W. Rees, Eds., Pergamon Press, New York, 1984, Vol. 6, pp 235-332.

The compounds of the formula V where W is W1, W2 or where W togetherwith R² is W3, with Q in each case being S, are particularlyadvantageously prepared by the method originally disclosed by Hantzsch(A. Hantzsch, J. H. Weber, Ber. Dtsch. Chem. Ges. 1887, 20, 3118), inwhich alpha-halo or alpha-hydroxy ketones are reacted with thioamides togive the corresponding thiazoles V according to the reaction conditionsdescribed in the experimental section.

In the case where W represents a radical W1, W2 or together with R² aradical W3, with Q in each case being NH, the appropriate startingmaterials can either be purchased or prepared by methods as alreadymentioned. A general overview for the synthesis of substitutedimidazoles can be found in Houben-Weyl “Methoden der OrganischenChemie”, Vol. E8, Hetarenes III Part 3, Thieme-Verlag, Stuttgart; and M.R. Grimmett, Advances in Heterocyclic Chemistry 1970, 12, 103-83.

Phenyl- or hetaryl substituted imidazole compounds of the formula IIwith Q=NH are particularly advantageously prepared by a method disclosedin WO 2005/002503 and CA2027347A1, which is depicted in Scheme 4 with Yrepresented by phenyl as an example:3-Imino-2,3-dihydro-1H-isoindol-1-one is converted into 2-substituted3-imino-2-(2-oxo-2-ethyl)-2,3-dihydro-1H-isoindol-1-one by alkylationwith an alpha-halo-ketone, which upon basic treatment rearranges to thecorresponding 4-substituted 2-(-1H-imidazol-2-yl)benzoic acid.

In the case where W represents a radical W1, W2 or together with R² aradical W3, with Q in each case being O, the appropriate startingmaterials can either be purchased or prepared by methods as alreadymentioned. A general overview for the synthesis of substituted oxazolescan be found in Houben-Weyl “Methoden der Organischen Chemie”, Vol. E8,Hetarenes III Part 1, Thieme-Verlag, Stuttgart; or D. C. Palmer, Ed.“Oxazoles: The Chemistry of Heterocyclic compounds”, Part A, Vol. 60,Wiley, New York, 2003.

According to one aspect of the invention the hydrogen atom linked to thecarbon atom carrying the radical R¹ of a compound I is replaced by adeuterium atom, as shown in formula I-D below. R¹, R², R^(3a), R^(3b),Y¹, Y², Y³, Y⁴, W and X in formula I-D have the aforementioned meanings.

Compounds of formula I-D can be prepared in analogy to methods describedby F. Maltais et al., J. Med. Chem. 2009, 52 (24), 7993-8001 (DOI10.1021/jm901023f). The degree of deuteration at said position usuallyexceeds 80%, preferably exceeds 90% and in particular exceeds 95%. Thedeuterated compounds of formula I-D often show a markedly higherstability against racematisation than their counterparts of formula I,probably due to a kinetic isotope effect (see F. Maltais et al., J. Med.Chem. 2009, 52 (24), 7993-8001).

The reaction mixtures are worked up in a conventional way, e.g. bymixing with water, separating the phases and, where appropriate,purifying the crude products by chromatography. The intermediates andfinal products in some cases result in the form of colorless or palebrownish, viscous oils which are freed of volatiles or purified underreduced pressure and at moderately elevated temperature. If theintermediates and final products are obtained as solids, thepurification can also take place by recrystallization or digestion.

If individual compounds I are not obtainable by the routes describedabove, they can be prepared by derivatization of other compounds I.

The compounds of the invention exhibit extremely low Ki values inrelation to the inhibition of calpain and thus permit efficientinhibition of calpain, especially calpain I, at low serum levels. Thecompounds of the invention ordinarily exhibit Ki values in relation tothe inhibition of calpain in vitro of <500 nM, in particular <100 nM andspecifically ≦40 nM. The compounds of the invention are thereforeparticularly suitable for the treatment of disorders associated with anelevated calpain activity.

In addition, the compounds of the invention are selective calpaininhibitors, i.e. the inhibition of other cysteine proteases such ascathepsin B, cathepsin K, cathepsin L or cathepsin S takes place only atconcentrations which are distinctly higher than the concentrationsnecessary for inhibition of calpain. Accordingly, the compounds of theinvention ought to show distinctly fewer side effects than the prior artcompounds which are comparatively unselective in relation to inhibitionof calpain and likewise inhibit other cysteine proteases.

Compounds preferred according to the invention accordingly have aselectivity in relation to inhibition of cathepsin B, expressed in theform of the ratio of the Ki for inhibition of cathepsin B to the Ki forinhibition of calpain of ≧10, in particular ≧30.

Compounds preferred according to the invention accordingly have aselectivity in relation to inhibition of cathepsin K, expressed in theform of the ratio of the Ki for inhibition of cathepsin K to the Ki forinhibition of calpain of ≧10, in particular ≧30.

Compounds preferred according to the invention accordingly have aselectivity in relation to inhibition of cathepsin L, expressed in theform of the ratio of the Ki for inhibition of cathepsin L to the Ki forinhibition of calpain of ≧30, in particular ≧50.

Compounds preferred according to the invention accordingly have aselectivity in relation to inhibition of cathepsin S, expressed in theform of the ratio of the Ki for inhibition of cathepsin S to the Ki forinhibition of calpain of ≧50, in particular ≧100.

In addition, the compounds of the present invention feature an improvedstability in the cytosole of human cells, which markedly contributes totheir good overall metabolic stability. The cytosolic stability can bemeasured for example by incubating a solution of a compound of theinvention with liver cytosole from particular species (for example rat,dog, monkey or human) and determining the half-life of the compoundunder these conditions. It is possible to conclude from largerhalf-lives that the metabolic stability of the compound is improved. Thestability in the presence of human liver cytosole is of particularinterest because it makes it possible to predict the metabolicdegradation of the compound in the human liver. Compounds with enhancedcytosolic stability therefore are likely to be degraded at reduced ratesin the liver. Slower metabolic degradation in the liver in turn can leadto higher and/or longer-lasting concentrations (effective levels) of thecompound in the body, so that the elimination half-life of the compoundsof the invention is increased. Increased and/or longer-lasting effectivelevels may lead to a better efficacy of the compound in the treatment orprophylaxis of various calpain-dependent diseases. An improved metabolicstability may additionally lead to an increased bioavailability afteroral administration, because the compound is subjected, after beingabsorbed in the intestine, to less metabolic degradation in the liver(termed the first pass effect). An increased oral bioavailability may,because the concentration (effective level) of the compound isincreased, lead to a better efficacy of the compound after oraladministration.

Accordingly, due to their improved cytosolic stability the compounds ofthe invention remain in the cytosol for extended periods, i.e. have adecreased cytosolic clearance, and therefore ought to show enhancedhuman pharmacokinetics.

Compounds preferred according to the invention accordingly have acytosolic clearance in human liver cytosol of ≦30 μl/min/mg, inparticular of ≦15 μl/min/mg.

The improved cytosolic stability of the compounds according to thepresent invention is probably primarily due to their reducedsusceptibility to aldo-keto reductases (AKRs) which mediate themetabolic degradation of compounds having a carbonyl group in the livercytosole of humans and monkeys. Thus, the AKR-catalyzed reduction of theketoamides of formula I should be less pronounced than that of lessstable ketoamides. Hence, the ratio of the concentration of the parentcompound, i.e. the ketamide of formula I, to the concentration of themetabolite, i.e. the hydroxyamide stemming form the ketoamide, is ameasure for the stability of the compounds of the invention.

Compounds preferred according to the invention accordingly have, afteran incubation in human hepatocytes for 4 hours, a concentration ratio ofthe hydroxyamide metabolite to their corresponding parent compound offormula I of ≦5, in particular ≦2 and specifically ≦0.5.

Owing to their inhibitory effect on calpain and their selectivity forcalpain by comparison with other cysteine proteases, the compounds ofthe invention of the formula I, their tautomers and theirpharmaceutically suitable salts are particularly suitable for thetreatment of a disorder, of an impairment or of a condition which isassociated with an elevated calpain activity as are described forexample in the prior art cited at the outset.

Disorders, impairments or conditions associated with an elevated calpainactivity are in particular neurodegenerative disorders, especially thoseneurodegenerative disorders occurring as a result of a chronic brainsupply deficit, of an ischemia (stroke) or of a trauma such as braintrauma, and the neurodegenerative disorders Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis and Huntington'sdisease, also multiple sclerosis and the damage to the nervous systemassociated therewith, especially damage to the optic nerve (opticneuritis) and the nerves which control the movement of the eye.Accordingly, preferred embodiments of the invention relate to thetreatment of neurodegenerative disorders, especially of theaforementioned neurodegenerative disorders in humans, and to the use ofthe compounds of the invention of the formula I, their tautomers andtheir pharmaceutically suitable salts for the manufacture of amedicament for the treatment of these disorders.

Disorders, impairments or conditions associated with an elevated calpainactivity also include epilepsy. Accordingly, preferred embodiments ofthe invention relate to the treatment of epilepsy in humans, and to theuse of the compounds of the invention of the formula I, their tautomersand their pharmaceutically suitable salts for the manufacture of amedicament for the treatment of epilepsy.

The disorders, impairments or conditions associated with an elevatedcalpain activity also include pain and painful conditions. Accordingly,preferred embodiments of the invention relate to the treatment of painand painful conditions in mammals, especially in humans, and to the useof the compounds of the invention of the formula I, their tautomers andtheir pharmaceutically suitable salts for the manufacture of amedicament for the treatment of pain and painful conditions.

The disorders, impairments or conditions associated with an elevatedcalpain activity also include damage to the heart following cardiacischemias, damage to the kidneys following renal ischemias, skeletalmuscle damage, muscular dystrophies, damage arising throughproliferation of smooth muscle cells, coronary vasospasms, cerebralvasospasms, macular degeneration, cataracts of the eyes, or restenosisof blood vessels following angioplasty. Accordingly, preferredembodiments of the invention relate to the treatment of diseases orconditions associated with damage to the heart following cardiacischemias, damage to the kidneys following renal ischemias, skeletalmuscle damage, muscular dystrophies, damage arising throughproliferation of smooth muscle cells, coronary vasospasms, cerebralvasospasms, macular degeneration, cataracts of the eyes, or restenosisof blood vessels following angioplasty in mammals, especially in humans,and to the use of the compounds of the invention of the formula I, theirtautomers and their pharmaceutically suitable salts for the manufactureof a medicament for the treatment of these disorders.

It has further emerged that inhibition of calpain brings about cytotoxiceffects on tumor cells. Accordingly, the compounds of the invention aresuitable for the chemotherapy of tumors and metastasis thereof.Preferred embodiments of the invention therefore relate to the use ofthe compounds of the invention of the formula I, their tautomers andtheir pharmaceutically suitable salts in the therapy of tumors andmetastases, and to their use for the manufacture of a medicament for thetherapy of tumors and metastases.

It has further been found that various impairments associated with anHIV disorder, especially nerve damage (HIV-induced neurotoxicity), aremediated by calpain and therefore inhibition of calpain allows suchimpairments to be treated or alleviated. Accordingly, the compounds ofthe invention of the formula I, their tautomers and theirpharmaceutically suitable salts are suitable for the treatment of HIVpatients. Preferred embodiments of the invention therefore relate to theuse of the compounds of the invention of the formula I, their tautomersand their pharmaceutically suitable salts for the treatment ofHIV-infected patients, especially the treatment of those impairmentscaused by an HIV-induced neurotoxicity, and to their use for themanufacture of a medicament for the treatment of HIV patients.

It has further been found that the release of interleukin-I, TNF orbeta-amyloid peptides (AB or AB-peptides) can be reduced or completelyinhibited by calpain inhibitors. Accordingly, impairments or disordersassociated with an elevated interleukin-I, TNF or Aβ level can betreated by using the compounds of the invention of the formula I, theirtautomers and their pharmaceutically suitable salts. Preferredembodiments of the invention therefore relate to the use of thecompounds of the invention of the formula I, their tautomers, theirprodrugs and their pharmaceutically acceptable salts for the treatmentof impairments or disorders associated with an elevated interleukin-I,TNF or Aβ level such as rheumatism, rheumatoid arthritis and to theiruse for the manufacture of a medicament for the treatment of suchimpairments or disorders.

The compounds of the general formula (I) are distinguished in particularalso by a good metabolic stability. The metabolic stability of acompound can be measured for example by incubating a solution of thiscompound with liver microsomes from particular species (for example rat,dog or human) and determining the half-life of the compound under theseconditions (R S Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). Itis possible to conclude from larger half-lives that the metabolicstability of the compound is improved. The stability in the presence ofhuman liver microsomes is of particular interest because it makes itpossible to predict the metabolic degradation of the compound in thehuman liver. Compounds with increased metabolic stability are thereforeprobably also degraded more slowly in the liver (measured in the livermicrosome test). Slower metabolic degradation in the liver can lead tohigher and/or longer-lasting concentrations (effective levels) of thecompound in the body, so that the elimination half-life of the compoundsof the invention is increased. Increased and/or longer-lasting effectivelevels may lead to a better efficacy of the compound in the treatment orprophylaxis of various calpain-dependent diseases. An improved metabolicstability may additionally lead to an increased bioavailability afteroral administration, because the compound is subjected, after beingabsorbed in the intestine, to less metabolic degradation in the liver(termed the first pass effect). An increased oral bioavailability may,because the concentration (effective level) of the compound isincreased, lead to a better efficacy of the compound after oraladministration.

The compounds of the invention of the formula I are furtherdistinguished by exhibiting an improved pharmacological activity,compared with the carboxamide compounds of the formula I disclosed inthe prior art, in patients or relevant animal models allowing prognosticstatements for use in treatment.

The present invention also relates to pharmaceutical compositions (i.e.medicaments) which comprise at least one compound of the invention ofthe formula I or a tautomer or a pharmaceutically suitable salt thereofand, where appropriate, one or more suitable excipients/drug carriers.

These drug carriers/excipients are chosen according to thepharmaceutical form and the desired mode of administration.

The compounds of the invention of the general formula I, their tautomersand the pharmaceutically suitable salts of these compounds can be usedto manufacture pharmaceutical compositions for oral, sublingual,subcutaneous, intramuscular, intravenous, topical, intratracheal,intranasal, transdermal or rectal administration, and be administered toanimals or humans in unit dose forms, mixed with conventionalpharmaceutical carriers, for the prophylaxis or treatment of the aboveimpairments or diseases.

Suitable unit dose forms include forms for oral administration, such astablets, gelatin capsules, powders, granules and solutions orsuspensions for oral intake, forms for sublingual, buccal, intratrachealor intranasal administration, aerosols, implants, forms of subcutaneous,intramuscular or intravenous administration and forms of rectaladministration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active basic ingredient may vary between 0.01 and 50 mg perkg of body weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose can be administered 1 to 5 times a day, so thata daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the mainingredient is mixed with a pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets may be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display aprolonged or delayed activity and in order to release a predeterminedamount of the active basic ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and taking up the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may comprise active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloring.

The water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agentssuch as polyvinylpyrrolidones, and sweeteners or taste improvers.

Rectal administration is achieved by the use of suppositories which areprepared with binders which melt at the rectal temperature, for examplecocobutter or polyethylene glycols. Parenteral administration iseffected by using aqueous suspensions, isotonic salt solutions orsterile and injectable solutions which comprise pharmacologicallysuitable dispersants and/or wetting agents, for example propylene glycolor polyethylene glycol.

The active basic ingredient may also be formulated as microcapsules orliposomes/centrosomes, if suitable with one or more carriers oradditives.

In addition to the compounds of the general formula I, their tautomersor their pharmaceutically suitable salts, the compositions of theinvention may comprise further active basic ingredients which may bebeneficial for the treatment of the impairments or diseases indicatedabove.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active basic ingredients arepresent together, where at least one thereof is a compound of theinvention.

The compounds of the invention also include those compounds in which oneor more atoms have been replaced by their stable, non-radioactiveisotopes, for example, a hydrogen atom by deuterium.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one additional neutron than the normally abundantisotope of the respective atom. Deuterated compounds have been used inpharmaceutical research to investigate the in vivo metabolic fate of thecompounds by evaluation of the mechanism of action and metabolic pathwayof the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64,3, 367-391 (1975)). Such metabolic studies are important in the designof safe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

Incorporation of a heavy atom particularly substitution of deuterium forhydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug. This effect is usually insignificant ifthe label is placed at a metabolically inert position of the molecule.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

The following examples illustrate the invention without restricting it.Depending on the management of the reaction and work up, the compoundsof the general formula I result as mixtures of carbonyl form and thecorresponding hydrates. Conversion into the pure carbonyl compoundsgenerally takes place by treating the substances with HCl in an inertsolvent.

EXAMPLES Preparation Examples Example 1N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1H-benzimidazol-2-yl)pyridine-3-carboxamide1.1 2-(1H-Benzo[d]imidazol-2-yl)nicotinic acid

A mixture of furo[3,4-b]pyridine-5,7-dione (2.0 g, 13.41 mmol) andbenzene-1,2-diamine (1.45 g, 13.41 mmol) in 20 ml ofN,N-dimethylformamide (DMF) was heated to 100° C. for 3 hours. Thereaction mixture was evaporated to dryness, the obtained residue takenup in 15 mL of dichloromethane and stirred for 30 minutes at 5° C.Filtration with suction and drying gave 1.0 g of a red solid, which wasused further without additional purification.

ESI-MS [M+H]⁺=240.1.

1.2(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(1H-benzo[d]imidazol-2-yl)nicotinamide

0.2 g N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDC), 1.04 g 1-hydroxybenzotriazole hydrate and 150 μL triethylamine(Et₃N) were successively added to a solution of2-(1H-benzo[d]imidazol-2-yl)nicotinic acid (0.2 g. 0.836 mmol) and3-amino-2-hydroxy-4-phenylbutanamide (170 mg, 0.875 mmol) in 40 ml ofdichloromethane at 5° C., and the mixture was stirred at 5° C. for about5 minutes. A pH of 8-9 was adjusted by adding of 50 μl Et₃N, the mixturestirred for 1 hour at 5° C. and then overnight at room temperature. Forwork up the reaction mixture was evaporated to dryness, treated with 50ml of water, the precipitate filtered off with suction, washed threetimes with water and dried at 50° C. over night. The crude product waspurified by crystallization from 10 ml of 2-propanole yielding 50 mg ofthe title compound as white amorphous solid.

ESI-MS [M+H]⁺=416.2.

1.3N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1H-benzimidazol-2-yl)pyridine-3-carboxamide

160 mg of EDC and 36 μL of 2,2-dichloroacetic acid were added to 42 mgN-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(1H-benzo[d]imidazol-2-yl)nicotinamide(0.096 mmol) in 2 ml of dry dimethylsulfoxide (DMSO), and the reactionmixture stirred for 25 minutes at room temperature. For work up thereaction mixture was mixed with 40 ml of NaCl solution and sat. NaHCO₃(1:1) for 10 minutes. The resulting solid was filtered off with suction,washed with water and dried. 24 mg of the title compound were obtainedas lightgrey amorphous solid.

ESI-MS [M+H]⁺=414.1.

¹H-NMR (500 MHz DMSO) δ ppm 13.0 (s broad, 1H), 9.55 (m, 1H), 8.78 (m,2H), 8.02 (s, 1H), 7.81 (m, 1H), 7.6-7.5 (m, 3H), 7.3-6.90 (m, 6H), 5.51(m, 1H), 3.21 (m, partially superimposed by water), 3.06 (m, 1H).

Example 2N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine-3-carboxamide2.17-Imino-6-(2-oxo-2-phenylethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a suspension of 7-imino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(147 mg, 1 mmol) and 2-bromoacetephenone (219 mg, 1.1 mmol) in 3 ml ofacetone K₂CO₃ (276 mg, 2.0 mmol) und KI (100 mg, 0.60 mmol) were added,and the mixture stirred over night. After filtration the mother liquorwas evaporated to dryness, the obtained residue was treated with 30 mlof methyl-tert.-butylether, filtrated and dried to give 140 mg of thetitle compound as amorphous solid.

¹H-NMR (500 MHz DMSO) δ ppm 9.96 (s, 1H), 9.02 (dd, 1H), 8.34 (dd, 1H),8.1 (m, 2H), 7.81 (dd, 1H), 7.74 (m, 1H), 7.61 (m, 2H), 5.35 (s, 2H).

2.2 2-(5-Phenyl-1H-imidazol-2-yl)nicotinic acid

To the suspension of7-imino-6-(2-oxo-2-phenylethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(825 mg, 3.11 mmol) in 1N NaOH (6.22 ml) 40 ml of water were added, andthe reaction mixture heated to reflux for 1.5 hours. After cooling toroom temperature the mixture was diluted with 100 ml of water, and thepH adjusted to 2-3 by addition of 2N HCl. The resulting precipitate wasfiltered off and dried to give 414 mg of the title compound as solid;ESI-MS [M+H⁺]: 266.1.

¹H-NMR (500 MHz DMSO) δ ppm 14.01 (s broad), 8.81 (dd, 1H), 8.48 (dd,1H), 7.94 (s, 1H), 7.85 (m, 1H), 7.83 (m, 1H), 7.59 (dd, 1H), 7.46 (m,2H), 7.32 (m, 1H).

2.3N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)nicotinamide

Coupling of 2-(5-phenyl-1H-imidazol-2-yl)nicotinic acid (200 mg, 0.754mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (161 mg, 0.829 mmol) in amanner analogous to example 1.2 afforded 142 mg of crude product, whichwas purified by chromatography on silica gel (eluent: CH₂Cl₂+0-20%methanol). After evaporation of the combined product fractions theremaining oil was treated with water, the resulting precipitate filteredoff and dried to give 55 mg of the title compound.

ESI-MS [M+H]⁺: 442.2.

2.4N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)nicotinamide

To a solution ofN-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)nicotinamide(60 mg, 0.136 mmol) in a mixture of 2 ml of DMSO and 10 ml ofdichloromethane IBX-polystyrene was added (371 mg, 0.408 mmol), and thereaction mixture stirred for 16 hours at room temperature. The polymerwas filtered off, washed with dichloromethane, the combined organiclayers washed with water, dried and evaporated to dryness. The remainingoily residue was treated with water to give a yellow solid which wasfiltered off and dried again. To a solution of the obtained solid in 20ml of ethylacetate (EtOAc) two drops of 4N HCl in dioxane were added,and the resulting precipitate filtered off. Recrystallisation of thecrude product from 15 ml of ethylacetate yielded 31 mg of the titlecompound as solid.

ESI-MS [M+H₂O+H]⁺: 458.2.

¹H-NMR (500 MHz DMSO) δ ppm 9.55 (m, 1H), 8.86 (m, 1H), 8.04 (m, 2H),7.85 (m, 2H), 7.74 (m, 1H), 7.46 (m, 2H), 7.38 (m, 1H), 7.25-7.11 (m,6H), 5.50 (m, 1H), 3.7 and 2.90 (each dd, 1H).

Example 3N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide3.1N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide

0.58 g 1-Hydroxybenzotriazole hydrate, 0.75 ml diisopropylethylamin(DIPEA) and 0.82 g EDC successively were added to a solution of2-(1,3-benzothiazol-2-yl)benzoic acid (1.0 g, 3.90 mmol) in a mixture of1.5 ml DMF und 20 ml THF at 5° C., and stirred at 5° C. for 1 hour.3-Amino-2-hydroxy-4-phenylbutanamide (0.8 g, 3.9 mmol) was added, andthe reaction mixture stirred for 1 hour at 5° C. and then over night atroom temperature. For work up water was added under cooling, theprecipitate formed filtered off with suction and dried to give 1.33 g ofthe title compound.

ESI-MS [M+H]⁺=433.3.

3.1N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide

To a solution ofN-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide(0.5 g, 1.16 mmol) in 1.5 ml of DMSO und 15 ml of dichloromethane 3.04 gN-cyclohexylcarbodiimid-N′-methylpolystyrole (1.9 mmol/g; 5.78 mmol) and0.24 ml dichloroacetic acid (0.38 g, 2.89 mmol) were added, and thereaction mixture stirred over night at room temperature. For work up thepolymer was filtered off, washed with dichloromethane, and the combinedorganic layers evaporated to dryness. Treatment with a mixture ofn-hexane/ethylacetate, filtration and drying afforded 260 mg of thetitle compound, as white amorphous solid:

ESI-MS [M+H⁺]=431.04.

¹H-NMR (400 MHz DMSO) δ ppm: 9.06 (d, 1H), 8.74 (d, 1H), 8.12 (d, 1H),8.05 (s, 1H), 7.81 (d, 2H), 7.68 (d, 1H), 7.60 (dd, 1H), 7.48 (m, 2H),7.26 (d, 2H), 7.07-7.18 (m, 3H), 5.53-5.59 (m, 1H), 3.20 (dd, 1H), 2.94(dd, 1H).

Example 4N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]pyridine-3-carboxamide4.1 Ethyl 2-carbamothioylnicotinate

Et₃N (10 ml) was added to a solution of ethyl 2-cyanonicotinate (1.9 g,10.78 mmol) in 20 ml of pyridine. Hydrogen sulfide was passed throughthe reaction mixture at 5° C. for 20 minutes, then the mixture wasstirred for 1 hour at room temperature. For work up the solution waspurged with nitrogen for 30 minutes, evaporated to dryness, and theremaining solid dissolved in 200 ml of dichloromethane. The organiclayer was washed successively with water and brine, dried, evaporatedand treated with ethylacetate to give 2.15 g of a red oil which wasreacted without further purification.

ESI-MS [M+H]⁺: 211.1.

4.2 Ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinate

To a suspension of ethyl 2-carbamothioylnicotinate (1.9 g, 9.04 mmol) in20 ml of DMF 4-fluorophenacylbromide (2.0 g, 9.22 mmol) was added, andthe resulting mixture stirred for 2 hours at room temperature. Themixture was filtered under suction, the mother liquor evaporated todryness, and the remaining oil purified by chromatography on silica gel(eluent: CH₂Cl₂+0-5% methanol) to give 434 mg of the title compound asamorphous solid.

ESI-MS [M+H]⁺: 329.1.

4.3 2-(4-(4-Fluorophenyl)thiazol-2-yl) nicotinic acid

3 ml of a 2N NaOH solution were added to a solution of ethyl2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinate (430 mg, 1.31 mmol) in 25ml of methanol, and afterwards stirred for 2 hours at 60° C. Thereaction mixture was subsequently evaporated to dryness, mixed withwater and neutralized by adding 2N HCl. Filtration with suction anddrying the precipitate formed resulted in 356 mg of the acid as yellowamorphous solid.

ESI-MS [M+H]⁺: 301.05.

4.4N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinamide

Coupling of 2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinic acid (356 mg,1.185 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (280 mg, 1.442mmol) in an analogous manner as described for example 1.2 afforded 530mg of the title compound as white amorphous solid.

ESI-MS [M+H]⁺: 477.2.

¹H-NMR (500 MHz DMSO) δ ppm 8.69 (m, 1H), 8.22 (m, 2H), 8.01 (m, 2H),7.71 (m, 1H), 7.55 (m, 1H), 7.26-7.10 (m, 9H), 5.75 (m, 1H), 4.47 (m,1H), 3.82 (m, 1H), 2.80 (m, 2H).

4.5N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinamide

N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(4-(4-fluorophenyl)thiazol-2-yl)nicotin-amide(310 mg, 0.651 mmol) was oxidized in a manner analogous to example 1.3.The crude product obtained after work up was crystallized from2-propanole, the precipitate formed filtered off with suction and driedto give 205 mg of the title compound as white solid; ESI-MS [M+H+]:475.15.

¹H-NMR (500 MHz DMSO) δ ppm 8.96 (m, 1H), 8.69 (m, 1H), 8.22 (s, 1H),8.10 (s, 1H), 7.89 (m, 3 h), 7.58 (m, 2H), 7.23-7.10 (m, 7H), 5.70 (m,1H), 3.12 and 2.68 (each dd, 1H).

Example 5N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]pyridine-3-carboxamide5.1 2-(2-Bromoacetyl)-3-(methoxycarbonyl)pyridinium bromide

To a solution of methyl 2-acetylnicotinate (750 mg, 4.19 mmol)—preparedaccording to H. Nagano et al.; Heterocycles 1987, 26, 1263-1270—in 2 mlof 33% HBr in acetic acid a suspension of pyridinium bromide perbromide(1.4 g, 4.38 mmol) in 5 ml of acetic acid was added, and stirred for 5hours at room temperature. The precipitate formed was filtered off undersuction, washed with n-pentane and dried to give 1.17 g of the titlecompound.

5.2 Methyl 2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinate

To a solution of 2-(2-bromoacetyl)-3-(methoxycarbonyl)pyridinium bromide(1.17 g, 3.45 mmol) in 10 ml of DMF 4-fluorobenzothioamide (0.7 g, 4.51mmol) were added and stirred at room temperature over night. For work upthe reaction mixture was evaporated to dryness and the obtained crudeoil purified by chromatography on silica gel (eluent: CH₂CL₂+0.2%methanol) to give 865 mg of the thiazole as yellow oil.

ESI-MS [M+H]⁺: 315.05.

5.3 2-(2-(4-Fluorophenyl)thiazol-4-yl) nicotinic acid

5.5 ml of a 2N NaOH solution were added to a solution of methyl2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinate (850 mg, 2.7 mmol) in 30 mlof methanol, and afterwards stirred for 4 hours at 50° C. The reactionmixture was evaporated to dryness, mixed with water and neutralized byadding 2N HCl. Filtration with suction and drying the precipitate formedresulted in 690 mg of the acid as amorphous solid.

ESI-MS [M+H]⁺: 301.0.

5.4N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinamide

Coupling of 2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinic acid (350 mg,1.165 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (270 mg, 1.39 mmol)in an analogous manner as described for example 1.2 afforded 520 mg ofthe title compound as white amorphous solid; ESI-MS [M+H+]: 477.1.

¹H-NMR (500 MHz DMSO) δ ppm 8.68 (m, 1H), 8.28 (d, 1H), 7.96 (m, 3H),7.70 (m, 1H), 7.44 (m, 1H), 7.30-7.20 (m, 9H), 5.76 (d, 1H), 4.37 (m,1H), 3.83 (m, 1H), 2.82 and 2.67 (each m, 1H).

5.5N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinamide

N-(4-Amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-(4-fluorophenyl)thiazol-4-yl)nicotin-amide(350 mg, 0.734 mmol) was oxidized in a manner analogous to example 1.3.The crude product obtained after work up was crystallized from2-propanole, the precipitate formed filtered off with suction and driedto give 208 mg of the title compound as white solid.

ESI-MS [M+H]⁺: 475.1.

¹H-NMR (500 MHz DMSO) δ ppm: 8.86 (m, 1H), 8.68 (m, 1H), 8.11 (s, 2H),7.87 (m, 3H), 7.60 (m, 1H), 7.47 (m, 1H), 7.29 (m, 2H), 7.15 (m, 5H),5.55 (m, 1H), 3.10 and 2.81 (each dd, 1H).

The compounds of the following examples were prepared in a manneranalogous to the preparation of example 5, if not indicated otherwise:

Example 6N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-{2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}pyridine-3-carboxamide

ESI-MS [M+H]⁺: 525.0.

¹H-NMR (500 MHz DMSO) δ ppm: 8.82 (m, 1H), 8.71 (m, 1H), 8.19 (s, 1H),8.01 (m, 2H), 7.81 (m, 2H), 7.68 (m, 2H), 7.49 (m, 1H), 7.1-7.0 (m, 5H),5.41 (m, 1H), 3.1 and 2.68 (each dd, 1H).

Example 7N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyl-1,3-thiazol-4-yl)pyridine-3-carboxamide

ESI-MS [M+H]⁺: 457.2.

¹H-NMR (500 MHz DMSO) δ ppm: 8.86 (m, 1H), 8.69 (m, 1H), 8.10 (s, 1H),8.05 (s, 1H), 7.83 (m, 3H), 7.62 (m, 1H), 7.44 (m, 4H), 7.15 (m, 5H),5.56 (m, 1H), 3.12 and 2.75 (each dd, 1H).

Example 8N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(2-chlorophenyl)-1,3-thiazol-4-yl]pyridine-3-carboxamide

ESI-MS [M+H]⁺: 491.1.

¹H-NMR (500 MHz DMSO) δ ppm: 8.82 (d, 1H), 8.70 (m, 1H), 8.30 (s, 1H),8.12 (, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.63 (m, 2H), 7.48 (m, 2H),7.38 (m, 1H), 7.0 (m, 5H), 5.52 (m, 1H), 3.08 and 2.69 (each dd, 1H).

Example 9N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(naphthalen-2-yl)-1,3-thiazol-4-yl]pyridine-3-carboxamide

ESI-MS [M+H]⁺: 507.2.

¹H-NMR (500 MHz DMSO) δ ppm: 8.92 (m, 1H), 8.71 (m, 1H), 8.47 (s, 1H),8.15 (s, 1H), 8.08 (m, 2H), 7.98 (m, 3H), 7.83 (s, 1H), 7.63 (m, 3H),7.49 (m, 1H), 7.12 (m, 2H), 7.05 (m, 3H), 5.61 (m, 1H), 3.11 and 2.76(each dd, 1H).

Example 10N-(1-Amino-1,2-dioxoheptan-3-yl)-2-(2-phenylthiazol-4-yl)nicotinamide

ESI-MS [M+H]⁺: 423.1.

¹H-NMR (500 MHz DMSO) δ ppm: 8.69 (m, 1H), 8.65 (d, 1H), 8.23 (s, 1H),7.98 (s, 1H), 7.93 (m, 2H), 7.28 (m, 2H), 7.55 (m, 4H), 5.18 (m, 1H),1.68 (m, 1H), 1.43 (m, 1H), 1.13 (m, 4H), 0.68 (m, 3H).

Example 11N-(1-Amino-1,2-dioxoheptan-3-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide11.1N-(1-Amino-2-hydroxy-1-oxoheptan-3-yl)-2-(2-phenylthiazol-4-yl)benzamide

Coupling of 2-(2-phenylthiazol-4-yl)benzoic acid (200 mg, 0.711 mmol)and 1-amino-2-hydroxy-1-oxoheptan-3-aminium chloride (145 mg, 0.737mmol) in an analogous manner as described for example 1.2 afforded 264mg of the title compound as white solid.

ESI-MS [M+H]⁺: 424.15.

11.2N-(1-Amino-1,2-dioxoheptan-3-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide

N-(1-Amino-2-hydroxy-1-oxoheptan-3-yl)-2-(2-phenylthiazol-4-yl)benzamide(120 mg, 0.283 mmol) was oxidized in a manner analogous to example 1.3.Recrystallization of the crude product in 2-propanole gave 50 mg of thetitle compound.

ESI-MS [M+H]⁺: 422.1.

¹H-NMR (500 MHz DMSO) δ ppm: 8.66 (d, 1H), 7.98 (m, 3H), 7.89 (d, 1H),7.81 (s, 1H), 7.74 (s, 1H), 7.55-7.41 (m, 7H), 5.06 (m, 1H), 1.69 and1.45 (each m, 1H), 1.18 (m, 4H), 0.75 (m, 3H).

Example 12N-(4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide

Prepared in a manner analogous to the preparation of example 10 giving60 mg of the title compound as white solid.

ESI-MS [M+H]⁺: 456.1.

¹H-NMR (500 MHz DMSO) δ ppm: 8.90 (d, 1H), 8.09 (s, 1H), 7.92 (m, 3H),7.84 (s, 1H), 7.45-7.23 (m, 13H), 5.45 (m, 1H), 3.20 and 2.78 (each dd,1H).

Example 13N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide13.1 Ethyl2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoate

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (700mg, 3.65 mmol), 1-hydroxybenzotriazole hydrate (550 mg, 3.59 mmol) andN,N-diisopropylethylamine (DIPEA) (1.2 ml, 6.87 mmol) were successivelyadded to a solution of (2-phenylthiazol-4-yl)nicotinic acid (820 mg,2.90 mmol) and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride(800 mg, 3.08 mmol) in dichloromethane (70 ml) at 5° C., and the mixturestirred at 5° C. for about 5 minutes. A pH of 8 was adjusted by adding0.6 ml of DIPEA, the mixture stirred for 1 hour at 5° C. and thenovernight at room temperature. The mixture then was concentrated underreduced pressure, poured into 200 ml of water, the precipitate formedwas filtered off with suction and dried in vacuo to give 1.33 g of thetitle product as white amorphous solid.

¹H-NMR (400 MHz DMSO) δ [ppm]: 8.68 (m, 1H), 8.23 (m, 1H), 7.96 (m, 2H),7.86 (s, 1H), 7.65 (dd, 1H), 7.40 (m, 3H), 7.17 (m, 5H), 5.45 (d, 1H),4.42 (m, 1H), 3.99 (m, 3H), 2.82 and 2.66 (each m, 1H), 1.12 (m, 3H).

13.2 2-Hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoicacid

To a solution of ethyl2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)-butanoate(1.31 g, 2.69 mmol) in THF (40 ml) LiOH (0.14 g, 5.85 mmol) in water (10ml) was added at 10° C., the mixture stirred for 1 hour at roomtemperature and then for 2 hours at 60° C. The mixture then wasconcentrated under reduced pressure, water and 3 ml of 2n HCl added,poured into 300 ml of a mixture of dichloromethane and 5% acetone. Theorganic layer was dried, filtered and concentrated under reducedpressure to give 1.19 g of the title acid;

ESI-MS [M+H]⁺=460.1.

13.3N-(4-(Cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide

To a solution of2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid(230 mg, 0.501 mmol) and cyclopropylamine (40 μL, 0.570 mmol) indichloromethane (30 ml)2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU) (230 mg, 0.605 mmol) and DIPEA (100 μL, 0,605mmol) were added at 5° C. The mixture was stirred for 1 hour at 5° C.and then for 5 hours at room temperature. The mixture was concentratedunder reduced pressure, 40 ml of water added, the precipitate formedfiltered off with suction, washed with water and dried in vacuo to give227 mg of a white amorphous solid;

ESI-MS [M+H]⁺=499.2.

13.4N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide

EDC (700 mg, 3.65 mmol) and 2,2-dichloroacetic acid (120 μl, 1.46 mmol)were added to a solution ofN-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide(217 mg, 0.435 mmol) in dimethyl sulfoxide (DMSO) (4 ml), and thereaction mixture stirred for 10 min at room temperature. For work up thereaction mixture was mixed with 80 ml of sat. NaHCO₃-solution for 10minutes. The resulting solid was filtered off with suction, washed withwater and dried in vacuo to give 193 mg of the title product as whiteamorphous solid;

ESI-MS [M+H]⁺=497.1.

¹H-NMR (400 MHz DMSO), δ [ppm]: 8.84 (d, 1H), 8.72 (m, 2H), 8.11 (s,1H), 7.84 (m, 2H), 7.60 (m, 1H), 7.45 (m, 4H), 7.21 (m, 5H), 5.58 (m,1H), 3.09 (m, 1H), 2.70 (m 2H), 0.67 (m, 2H), 0.57 (m, 2H).

Example 14N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide14.1N-(3-Hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide

DIPEA (200 μl, 0.567 mmol) was added to a suspension of2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid(250 mg, 0.544 mmol) und O-methylhydroxylamine hydrochloride (90 mg,1.078 mmol) in dichloromethane (50 ml) at 5° C. After about 5 min2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU) (665 mg, 1.748 mmol) was added, the pHadjusted to 8 via addition of further DIPEA, and the mixture thenstirred for 1 h at 5° C. and then overnight at room temperature. Thendichloromethane (50 ml) was added, washed 2× with 10 ml of water andbrine, dried, filtered and concentrated to give 430 mg of the crudeproduct which was purified by chromatography on silica gel(dichloromethane+11-12% methanol. Concentration of the combinedfractions and drying afforded 224 mg of a white amorphous solid;

ESI-MS [M+H]⁺: 489.1.

14.2N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide

To polymer-supported IBX (Novabiochem, 1.1 mmol/g; 400 mg, 0.440 mmol)in dichloromethane (5 ml)N-(3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide(140 mg, 0.287 mmol) in 10 ml of dichloromethane was added and themixture shaken for 2 days at room temperature. IBX was added again twice(200 mg, 0.220 mmol) at intervals of 1 day. After another 4 days themixture was filtered and concentrated under reduced pressure to 135 mgof the crude product which was purified by chromatography on silica gel.The combined fractions were concentrated, the remainder treated withwater, filtered off with suction and dried to 84 mg of the desiredproduct;

ESI-MS [M+H]⁺: 489.1

¹H-NMR (400 MHz DMSO), δ [ppm]: 12.01 (s broad, 1H), 8.89 (s broad, 1H),8.68 (d, 1H), 8.02 (s, 1H), 7.84 (m, 2H), 7.61 (m, 1H), 7.45 (m, 4H),7.21 (m, 5H), 5.48 (m, 1H), 3.77 (s, 3H), 3.16 and 2.66 (each m, 1H).

Example 15N-(4-Amino-1-(4-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide

The title compound was prepared in a manner analogous to the preparationof example 5 yielding 146 mg of the title compound as a white solid;ESI-MS [M+H+]: 475.05.

¹H-NMR (500 MHz DMSO) δ ppm: 8.80 (d, 1H), 8.70 (m, 1H), 8.13 (s, 1H),8.03 (m, 1H), 7.82 (m, 2H), 7.65 (m, 1H), 7.47 (m, 5 h), 7.15 (m, 2 h),6.88 (m, 2H), 5.47 (m, 1H), 3.1 and 2.68 (each m, 1H).

Example 16N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(benzo[d]oxazol-2-yl)nicotinamide16.1 Ethyl 2-(benzo[d]oxazol-2-yl)nicotinate

A mixture of ethyl 2-chloronicotinate (100 mg, 0.539 mmol),2-(tributylstannyl)benzo[d]oxazole (314 mg, 0.539 mmol) and[1,1′-bis(diphenylphosphino) ferrocene]-dichloropalladium (II) (39.4 mg,0.054 mmol) in DMF (2 mL) was heated to 110° C. for 1 h by applyingmicrowave radiation to the mixture. The reaction was repeated on thesame scale and the thus obtained reaction mixtures obtained werecombined. Excess water and EtOAc were added. The organic layer wasseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with water and dried over MgSO₄. Purificationby flash column chromatography (EtOAc/DCM, gradient: 1-10% DCM) providedthe title compound (290 mg, 90%);

ESI-MS [M+H+]=269.1.

16.2 2-(benzo[d]oxazol-2-yl)nicotinic acid

NaOH (1.65 mL, 2M in water) was added to a solution of ethyl2-(benzo[d]oxazol-2-yl)nicotinate (290 mg, 0.973 mmol) in EtOH. Afterstirring for 3 h at room temperature the solvent was removed in vacuo.The residue was dissolved in water (4 mL) and dilute HCl (1.8 mL, 2M inwater) was added resulting in pH 2-3 of the mixture. The mixture wasextracted with dichloromethane. The combined organic layers were washedwith saturated aqueous NaCl solution and dried over MgSO4. Removal ofthe solvent provided the title compound (190 mg, 81%); ESI-MS[M+H+]=241.1.

16.3N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(benzo[d]oxazol-2-yl)nicotinamide

Coupling of 2-(benzo[d]oxazol-2-yl)nicotinic acid (190 mg, 0.791 mmol)and 3-amino-2-hydroxy-4-phenylbutanamide (169 mg, 0.780 mmol) wasperformed by analogy to the method described for example 1.2 using DIPEAinstead of triethylamine. The reaction yielded 279 mg of the titlecompound; ESI-MS [M+H+]=417.1.

16.4N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(benzo[d]oxazol-2-yl)nicotinamide

N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(benzo[d]oxazol-2-yl)nicotinamide(60 mg, 0.144 mmol) was oxidized by analogy to example 1.3. The crudeproduct was purified by flash column chromatography(dichloromethane/MeOH, gradient 1-9% MeOH) providing 8.5 mg of the titlecompound; ESI-MS [M+H+]=415.1.

¹H-NMR (500 MHz DMSO): δ ppm: 9.19 (d, 1H), 8.85 (d, 1H), 8.09 (s, 1H),7.84-7.71 (m, 5H), 7.51-7.44 (m, 2H), 7-29-7.17 (m, 5H), 5.48-5.46 (m,1H), 3.22-3.18 (m, 1H), 2.96-2.88 (m, 1H).

Example 17N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyloxazol-4-yl)nicotinamide17.1 2-phenyloxazol-4-yl trifluoromethanesulfonate

2-phenyloxazol-4-yl trifluoromethanesulfonate was prepared as describedby N. F. Langille, L. A. Dakin, J. S. Panek, Organic Letters 2002, 4,15, 2485.

17.2 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole wasprepared from 2-phenyloxazol-4-yl trifluoromethanesulfonate according tothe procedure published by H. Araki, T. Katoh, M. Inoue, Synlett 2006,4, 555.

17.3 Ethyl 2-(2-phenyloxazol-4-yl)nicotinate

[1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride (22 mg, 0.032 mmol) was added to a mixture ofethyl-2-chloronicotinate (120 mg, 0.647 mmol) and2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (220 mg,0.811 mmol) in dioxane (5 mL). After the addition of K₂CO₃ (402 mg,2.910 mmol) the reaction mixture was heated at 65° C. for 4 h and thenallowed to cool to room temperature. Water was added and the mixture wasextracted with EtOAc. The combined organic layers were washed with waterand dried (MgSO₄). Purification of the thus obtained raw product byflash column chromatography (dichloromethane/EtOAc, gradient 5-10%EtOAc) provided the title compound (80 mg, 42%); ESI-MS [M+H+]=295.1.

17.4 2-(2-phenyloxazol-4-yl)nicotinic acid

An aqueous solution of NaOH (0.27 mL, 2M in water, 0.54 mmol) was addedto a solution of ethyl 2-(2-phenyloxazol-4-yl)nicotinate (80 mg, 0.27mmol) in EtOH (2.7 mL). After stirring overnight at room temperature thesolvent was removed in vacuo, the residue was dissolved in water and HCl(2M in water) was added until pH ˜1 was obtained. The solvent wasremoved in vacuo and the crude product obtained was used without furtherpurification; ESI-MS [M+H+]=267.1.

17.5N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-phenyloxazol-4-yl)nicotinamide

Coupling of 2-(2-phenyloxazol-4-yl)nicotinic acid (120 mg, 60% pure,0.270 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (58 mg, 0.297 mmol)by analogy to the method of example 1.2 using DIPEA instead of NEt₃afforded 87 mg of the title compound; ESI-MS [M+H+]=443.2.

17.6N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyloxazol-4-yl)nicotinamide

N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-phenyloxazol-4-yl)nicotinamide(80 mg, 0.181 mmol) was oxidized by analogy to the method of exampleexample 1.3; ESI-MS [M+H+]=441.1.

¹H-NMR (400 MHz DMSO) δ ppm: 8.98 (d, 1H), 8.69 (dd, 1H), 8.40 (s, 1H),8.07, s, 1H), 7.92-7.90 (m, 2H), 7.84 (s, 1H), 7.63-7.61 (m, 1H), 7.55(m, 3H), 7.47-7.46 (m, 1H), 7.28-7.13 (m, 5H), 5.53-5.50 (m, 1H), 3.18(dd, 1H), 2.81 (dd, 1H).

Biological Investigation of Inhibition of Calpain and Cathepsins

The following solutions and buffers were employed:

-   -   HBS (for 40 ml): 800 μl 1M HEPES; 2.16 ml 100 mM KCl; 4.8 ml 1M        NaCl; 3.59 ml 5% glucose; 60 μl 1M MgSO₄; 400 μl 100 mM Na        pyruvate, 28.19 ml water; pH 7.2-7.5.    -   lysis buffer (for 20 ml): 400 μl 1M Tris pH 8.2; 2.74 ml 1M        NaCl; 520 μl 0.5M EDTA; 2 ml 10% triton X-100; 0.8 ml (=1:25)        CompletePlus (1 tablet/2 ml H₂O); 200 μl 100 mM Pefabloc; 13.34        ml water, pH 8.2.    -   TBST (10×) (for 11): 100 mM Tris (12.1 g); 1.5M NaCl (87 g); 1%        Tween 20 (10 g), adjusted to pH 8.

I Enzyme Inhibition In Vitro:

-   -   Testing for blockade of the corresponding enzymic activities was        carried out by means of kinetic fluorescence assays (excitation        390 nm, emission 460 nm).    -   Apparent Ki values were calculated from the experimentally        determined IC₅₀ values by the Cheng-Prussoff relation assuming a        reversible competitive enzyme inhibition. The Km values of the        substrates used under the assay conditions indicated above were:        90 μM (Z-Phe-Arg-AMC, cathepsin B), 10 μM (Z-Gly-Pro-Arg-AMC,        cathepsin K), 2 μM (Z-Phe-Arg-AMC, cathepsin L), and 30 μM        (Z-Val-Val-Arg-AMC, cathepsin S).    -   The indicated Ki values are averages of the inhibition constants        calculated on the basis of 2 to 4 independent dose-effect plots.    -   The following assays were used:    -   1. Calpain I:        -   20 nM calpain-1-isolated from human erythrocytes (Calbiochem            #208713), 100 μM Suc-Leu-Tyr-AMC (Bachem #1-1355) as            substrate in buffer with 62 mM imidazole, 0.3 mM CaCl₂,            0.10% CHAPS, 0.05% BSA, 1 mM DTT at pH 7.3 and room            temperature.    -   2. Cathepsin B:        -   0.25 nM cathepsin B—isolated from human liver (Calbiochem            #219362), 100 μM Z-Phe-Arg-AMC (Bachem #1-1160) as substrate            50 mM MES, 2 mM EDTA, 0.05% Brij 35, 2.5 mM L-cysteine, pH            6.0, room temperature.    -   3. Cathepsin K:        -   3 nM cathepsin K-activated from recombinant human            procathepsin K from E. coli (Calbiochem #342001), 10 μM            Z-Gly-Pro-Arg-AMC (Biomol #P-142) as substrate in 50 mM MES,            2 mM EDTA, 0.05% Brij 35, 2.5 mM L-cysteine, pH 6.0, room            temperature.    -   4. Cathepsin L:        -   1 nM cathepsin L—isolated from human liver (Calbiochem            #219402), 2 μM Z-Phe-Arg-AMC (Bachem #1-1160) as substrate            in 50 mM MES, 2 mM EDTA, 0.05% Brij 35, 2.5 mM L-cysteine,            pH 6.0, room temperature.    -   5. Cathepsin S:        -   0.5 nM recombinant human cathepsin S from E. coli            (Calbiochem #219343), 20 μM Z-Val-Val-Arg-AMC (Bachem            #1-1540) as substrate in 50 mM MES, 2 mM EDTA, 0.05% Brij            35, 2.5 mM L-cysteine, pH 6.0, room temperature.    -   The results of the in vitro determination are indicated in        Table 1. The following abbreviations are used in Table 1:    -   In the “Calpain activity” column, +++ stands for a calpain Ki        (Ki(calpain)) of ≦40 nM, and ++ means: 40 nM<Ki(Calpain)≦100 nM        and + means 100 nM<Ki(Calpain)≦300 nM.    -   The “Sel. cat. B” column indicates the Ki(cathepsin        B)/Ki(calpain) ratio. In this connection, ++ means a        Ki(cathepsin B)/Ki(calpain) ratio of ≧30 and + means        10≦Ki(cathepsin B)/Ki(calpain)<30.    -   The “Sel. cat. K” column indicates the Ki(cathepsin        K)/Ki(calpain) ratio. In this connection, ++ means a        Ki(cathepsin K)/Ki(calpain) ratio of ≧30 and + means        10≦Ki(cathepsin K)/Ki(calpain)<30.    -   The “Sel. cat. L” column indicates the Ki(cathepsin        L)/Ki(calpain) ratio. In this connection, ++ means a        Ki(cathepsin L)/Ki(calpain) ratio of ≧50 and + means        30≦Ki(cathepsin L)/Ki(calpain)<50.    -   The “Sel. cat. S” column indicates the Ki(cathepsin        S)/Ki(calpain) ratio. In this connection, ++ means a        Ki(cathepsin S)/Ki(calpain) ratio of ≧100 and + means        50≦Ki(cathepsin S)/Ki(calpain)<100.

TABLE 1 Calpain Sel Sel Sel Sel human cyno Example activity cat. B cat.K cat. L cat. S cytCL cytCL 2 + + 3 ++ + + ++ ++ 4 ++ + + ++ ++ 5 ++ + +++ 6 +++ ++ + ++ ++ 7 +++ ++ + ++ ++ 8 +++ ++ + ++ ++ 9 ++ ++ + ++ ++13 + ++ + + ++ ++ 14 + ++ ++ ++ ++ 15 ++ ++ + ++ ++ 16 + + + ++

II Spectrin Molt-4 Assay to Determine Cellular Calpain Inhibition:

-   -   The assay design and procedure were as disclosed by Chatterjee;        BMC 1998, 6, pp. 509-522; the EC₅₀ values are calculated from        the percentage degradation of spectrin as a function of the        dose.    -   Cell culture conditions: the molt-4 cells are maintained in RPMI        1640+Glutamax™ I medium (Gibco) with 10% FCS and 50 μg/ml        gentamicin at 37° C., 5% CO₂ and split 1:15 twice a week.    -   Preparation of the molt-4 cells: the cells are washed, counted        and taken up in a concentration of 1×10⁷ cells/ml in HBS buffer.    -   Dilution of the inhibitor substances: all the inhibitors are        dissolved in a concentration of 10⁻² M in DMSO. The stock        solution is then diluted 1:15 in DMSO (=6.67×10⁻⁴ M). Thereafter        the stock solution diluted 1:15 is diluted 1:4 in DMSO in two        steps (=1.67×10⁻⁴ M and 4.17×10⁻⁵ M). Thereafter, these three        solutions are further diluted 1:50 in HBS buffer to give        solutions having a concentration of 1.33×10⁻⁵ M, 3.36×10⁻⁶ M and        8.34×10⁻⁷ M.    -   Test mixture: for each mixture, 10⁶ cells (see above) are        introduced into a 1.5 ml Eppendorf tube. To these are added in        each case 150 μl of the diluted substances (final conc. 10-5 M;        2.5×10⁻⁶ M and 6.25×10⁻⁷ M) and thoroughly mixed. A negative        control and a positive control are used as controls. In this        case, initially only 150 μl of HBS buffer is pipetted onto the        cells. All the mixtures are incubated at 37° C., 5% CO₂ in an        incubator for 10 min. Thereafter, except for the negative        control, in each case CaCl₂ (final conc. 5 mM) and ionomycin        (final conc. 5 μM) are added, thoroughly mixed and incubated at        37° C., 5% CO₂ in an incubator for 30 min. Then centrifuge at        700 g for 5 min. The supernatants are discarded and the pellets        are taken up in 20 μl of lysis buffer. The mixtures are        subsequently placed on ice for 30-60 min and then centrifuged at        15000 g for 15 min. The supernatants are removed and put into        new Eppendorf tubes. The protein determination is then carried        out thereon, e.g. with a MicroBCA assay (Pierce).    -   SDS-PAGE electrophoresis: 10 μg of total protein from each        mixture are put into a new Eppendorf tube and, after pipetting        in the same volume of 2× Tris-glycine SDS sample buffer        (Invitrogen) and 1/10 volume of 1M DTT, thoroughly mixed and        heated at 95° C. for 15 min. The solutions are briefly        centrifuged and loaded onto a 6% SDS gel (Invitrogen). The gel        is run at 100V with 1× Tris-glycine laemmli buffer (Biomol)        until the lower band of the marker has reached the base of the        gel.    -   Western blotting: the gel is removed from the apparatus and        blotted onto nitrocellulose in 1× Tris-glycine transfer buffer        (Invitrogen)+20% methanol with 1.5 A/cm² in a FastBlot chamber        (Biometra) for 30 min. The nitrocellulose filter is removed,        briefly washed in TBST buffer and blocked in TBST/5% milk powder        for 1 h at RT (room temperature). The blocked nitrocellulose is        then incubated with an anti-spectrin Ab (Chemicon) (1:10000 in        TBST/5% milk powder) at RT for 3 h or at 4° C. overnight. The        nitrocellulose is washed 3× in TBST buffer. It is then incubated        with anti-mouse IgG (POD) antibody (Sigma) (1:10000 in TBST/5%        milk powder) at room temperature for 1 h.    -   The nitrocellulose is then washed 5× in TBST buffer. In the next        step, 5 ml of prepared solution of the SuperSignal® West Pico        chemiluminescence substrate (Pierce) are put on the filter and        incubated for 5 min. The nitrocellulose is then taken out of the        solution, gently dabbed dry and inserted into a development        folder film (Tropix). A digital image analysis system (VersaDoc,        Biorad) is used to record and quantify the ECL (QuantityOne),        and the percentage degradation of spectrin is calculated from        the data. Graph-pad prism is used to fit the percentage spectrum        degradation as a function of the dose to a sigmoidal dose-effect        plot (top fixed at 100% and bottom at 0%), and the EC 50% is        calculated.

III Assay for Determining Cytosolic Clearance of Compounds of Formula I:

-   -   For comparison purposes data measured with human liver cytosol        were contrasted with those obtained with cynomolgus monkey liver        cytosol.    -   0.5 μM of a compound to be tested was incubated with 1 mg/ml of        human liver cytosol as well as monkey liver cytosol at 37° C. in        0.5 M of phosphate buffer at pH 7.5 while shaking (commercial        sources: female cynomolgus liver cytosol from Tebu bio, human        liver cytosol from BDgentest).    -   In each case aliquots of 65 μl were taken after 0, 5, 10 and 15        min and transferred into wells of a wellplate which were        immediately filled with 130 μl of ethanol to stop the reaction.        The samples were kept frozen until analysis on a LC/MS/MS system        (Applied Biosystems SCIEX 4000).    -   Read out parameters were the loss of parent compounds, from        which the half life periods (T_(1/2)) were calculated from.        Based on these data the parameters cytosolic clearance (cytCL),        scaled clearance (CLs) and predicted clearance (CLp) were        calculated using the following equations:

cytCL=(ln 2/T _(1/2))×[cytosolic protein]×1000  1)

CLs=cytCL×[cytosolic yield]/1,000,000×60  2)

CLp=(CLs+hepatic plasma flow)/hepatic plasma flow/CLs  3)

-   -   To assess the stability of the compounds tested the clearance        ranges were adjusted to the hepatic plasma flow of the different        species according to the following scheme:    -   stable=from 0 to about ⅓ of the hepatic plasma flow;    -   moderately stable=from about ⅓ to about ⅔ of the hepatic plasma        flow;    -   instable=more than ⅔ of the hepatic plasma flow.    -   Based on this adjustment the following qualifiers were assigned        to evaluate the cytosolic stabilities of the compounds tested.        The cytCL data obtained this way for the inventive compounds are        depicted in the table below.

cynomolgus cytCL symbol human monkey (cyno) stable ++ 0-14 μl/min/mg0-18 μl/min/mg moderately + 14-70 μl/min/mg 18-90 μl/min/mg stableinstable − >70 μl/min/mg >90 μl/min/mg

1-33. (canceled)
 34. A carboxamide compound of the formula I

in which R¹ is hydrogen, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl,where the last 3 radicals mentioned may be partly or completelyhalogenated and/or have 1, 2 or 3 substituents R^(1a), C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, where a CH₂ group in the cycloalkyl moietyof the last two radicals mentioned may be replaced by O, NH, or S, ortwo adjacent C atoms may form a double bond, where the cycloalkyl moietymay further have 1, 2, 3 or 4 radicals R^(1b), aryl, hetaryl,aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, hetaryl-C₁-C₄-alkyl orhetaryl-C₂-C₆-alkenyl, where aryl and hetaryl in the last 6 radicalsmentioned may be unsubstituted or carry 1, 2, 3 or 4 identical ordifferent radicals R^(1c); where R^(1a) is selected independently of oneanother from OH, SH, COOH, CN, OCH₂COOH, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, COOR^(a1),CONR^(a2)R^(a3), SO₂NR^(a2)R^(a3), —NR^(a2)—SO₂—R^(a4),NR^(a2)—CO—R^(a5), SO₂—R^(a4) and NR^(a6)R^(a7), R^(1b) is selectedindependently of one another from OH, SH, COOH, CN, OCH₂COOH, halogen,phenyl which optionally has 1, 2 or 3 substituents R^(1d), C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkylthio, where the alkyl moieties in the last 3substituents mentioned may be partly or completely halogenated and/orhave 1, 2 or 3 substituents R^(1a), COOR^(b1), CONR^(b2)R^(b3),SO₂NR^(b2)R^(b3), NR^(b2)—SO₂—R^(b4), NR^(b2)—CO—R^(b5), SO₂—R^(b4) andNR^(b6)R^(b7), in addition two R^(1b) radicals may together form aC₁-C₄-alkylene group, or 2 R^(1b) radicals bonded to adjacent C atoms ofcycloalkyl may form together with the carbon atoms to which they arebonded also a benzene ring, R^(1c) is selected independently of oneanother from OH, SH, halogen, NO₂, NH₂, CN, COOH, OCH₂COOH, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄ alkyl, C₁-C₆-alkylthio, where the alkylmoieties in the last 4 substituents mentioned may be partly orcompletely halogenated and/or have 1, 2 or 3 substituents R^(1a),C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-cycloalkyloxy,where the cycloalkyl moiety of the last three radicals mentioned mayhave 1, 2, 3 or 4 R^(1b) radicals, and where 1 or 2 CH₂-groups in thecycloalkyl moiety may be replaced by O, NH or S, aryl, hetaryl, O-aryl,and O—CH₂-aryl, where the last three radicals mentioned areunsubstituted in the aryl moiety or may carry 1, 2, 3 or 4 radicalsselected from the group consisting of R^(1d), COOR^(c1),CONR^(c2)R^(c3), SO₂NR^(c2)R^(c3), NR^(c2)—SO₂—R^(c4), NR^(c2)—CO—R⁵,SO₂—R^(c4), —(CH₂)_(p)—NR^(c6)R^(c7) with p=0, 1, 2, 3, 4, 5 or 6, andO—(CH₂)_(q)—NR^(c6)R^(c7) with q=2, 3, 4, 5 or 6; where R^(a1), R^(b1)and R^(c1) are independently H, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkyl which has 1, 2 or 3 substituents independently selected fromOH, SH, COOH, CN, OCH₂COOH, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, COOH,C(O)OC₁-C₆-alkyl, C(O)OC₁-C₆-haloalkyl, C(O)O—C₂-C₆-alkenyl,C(O)O—C₂-C₆-alkynyl, C(O)O—C₃-C₇-cycloalkyl, C(O)O-aryl, C(O)O-hetaryl,CONH₂, CON(H)C₁-C₆-alkyl, CON(C₁-C₆-alkyl)₂, CON(H)C₁-C₆-haloalkyl,CON(C₁-C₆-haloalkyl)₂, CON(C₁-C₆-alkyl)C₁-C₆-haloalkyl, SO₂NH₂,SO₂N(H)C₁-C₆-alkyl, SO₂N(C₁-C₆-alkyl)₂, SO₂N(H)C₁-C₆-haloalkyl,SO₂N(C₁-C₆-haloalkyl)₂, SO₂N(C₁-C₆-alkyl)C₁-C₆-haloalkyl,—NH—SO₂—C₁-C₆-alkyl, —NH—SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-alkyl)-SO₂—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-alkyl, N(H)—CO—C₁-C₆-alkyl,N(H)—CO—C₁-C₆-haloalkyl, N(C₁-C₆-alkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-haloalkyl, SO₂—C₁-C₆-alkyl,SO₂—C₁-C₆-haloalkyl, NH₂, N(H)(C₁-C₆-alkyl), N(H)(C₁-C₆-haloalkyl),N(C₁-C₆-alkyl)₂, N(C₁-C₆-alkyl) (C₁-C₆-haloalkyl), andN(C₁-C₆-haloalkyl)₂; C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄-alkyl, hetaryl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(1d),R^(a2), R^(b2) and R^(c2) are independently of one another H,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3substituents independently selected from OH, SH, COOH, CN, OCH₂COOH,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, COOH, C(O)OC₁-C₆-alkyl, C(O)OC₁-C₆-haloalkyl,C(O)O—C₂-C₆-alkenyl, C(O)O—C₂-C₆-alkynyl, C(O)O—C₃-C₇-cycloalkyl,C(O)O-aryl, C(O)O-hetaryl, CONH₂, CON(H)C₁-C₆-alkyl, CON(C₁-C₆-alkyl)₂,CON(H)C₁-C₆-haloalkyl, CON(C₁-C₆-haloalkyl)₂,CON(C₁-C₆-alkyl)C₁-C₆-haloalkyl, SO₂NH₂, SO₂N(H)C₁-C₆-alkyl,SO₂N(C₁-C₆-alkyl)₂, SO₂N(H)C₁-C₆-haloalkyl, SO₂N(C₁-C₆-haloalkyl)₂,SO₂N(C₁-C₆-alkyl) C₁-C₆-haloalkyl, —NH—SO₂—C₁-C₆-alkyl,—NH—SO₂—C₁-C₆-haloalkyl, —N(C₁-C₆-alkyl)-SO₂—C₁-C₆-alkyl,—N(C₁-C₆-alkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-alkyl, N(H)—CO—C₁-C₆-alkyl,N(H)—CO—C₁-C₆-haloalkyl, N(C₁-C₆-alkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-haloalkyl, SO₂—C₁-C₆-alkyl,SO₂—C₁-C₆-haloalkyl, NH₂, N(H)(C₁-C₆-alkyl), N(H)(C₁-C₆-haloalkyl),N(C₁-C₆-alkyl)₂, N(C₁-C₆-alkyl) (C₁-C₆-haloalkyl), andN(C₁-C₆-haloalkyl)₂; C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄ alkyl, hetaryl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(1d), andR^(a3), R^(b3) and R^(c3) are independently of one another H,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3substituents independently selected from OH, SH, COOH, CN, OCH₂COOH,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, COOH, C(O)OC₁-C₆-alkyl, C(O)OC₁-C₆-haloalkyl,C(O)O—C₂-C₆-alkenyl, C(O)O—C₂-C₆-alkynyl, C(O)O—C₃-C₇-cycloalkyl,C(O)O-aryl, C(O)O-hetaryl, CONH₂, CON(H)C₁-C₆-alkyl, CON(C₁-C₆-alkyl)₂,CON(H)C₁-C₆-haloalkyl, CON(C₁-C₆-haloalkyl)₂,CON(C₁-C₆-alkyl)C₁-C₆-haloalkyl, SO₂NH₂, SO₂N(H)C₁-C₆-alkyl,SO₂N(C₁-C₆-alkyl)₂, SO₂N(H)C₁-C₆-haloalkyl, SO₂N(C₁-C₆-haloalkyl)₂,SO₂N(C₁-C₆-alkyl) C₁-C₆-haloalkyl, —NH—SO₂—C₁-C₆-alkyl,—NH—SO₂—C₁-C₆-haloalkyl, —N(C₁-C₆-alkyl)-SO₂—C₁-C₆-alkyl,—N(C₁-C₆-alkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-alkyl, N(H)—CO—C₁-C₆-alkyl,N(H)—CO—C₁-C₆-haloalkyl, N(C₁-C₆-alkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-haloalkyl, SO₂—C₁-C₆-alkyl,SO₂—C₁-C₆-haloalkyl, NH₂, N(H)(C₁-C₆-alkyl), N(H)(C₁-C₆-haloalkyl),N(C₁-C₆-alkyl)₂, N(C₁-C₆-alkyl) (C₁-C₆-haloalkyl), andN(C₁-C₆-haloalkyl)₂; C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄ alkyl, hetaryl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(1d), orthe two radicals R^(a2) and R^(a3), or R^(b2) and R^(b3), or R^(c2) andR^(c3), form together with the N atom a 3 to 7-membered, optionallysubstituted nitrogen heterocycle which may optionally have 1, 2 or 3further different or identical heteroatoms selected from the groupconsisting of O, N, and S as ring members, R^(a4), R^(b4) and R^(c4) areindependently of one another C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkylwhich has 1, 2 or 3 substituents independently selected from OH, SH,COOH, CN, OCH₂COOH, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₃-C₇-cycloalkyloxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, COOH, C(O)OC₁-C₆-alkyl,C(O)OC₁-C₆-haloalkyl, C(O)O—C₂-C₆-alkenyl, C(O)O—C₂-C₆-alkynyl,C(O)O—C₃-C₇-cycloalkyl, C(O)O-aryl, C(O)O-hetaryl, CONH₂,CON(H)C₁-C₆-alkyl, CON(C₁-C₆-alkyl)₂, CON(H)C₁-C₆-haloalkyl,CON(C₁-C₆-haloalkyl)₂, CON(C₁-C₆-alkyl)C₁-C₆-haloalkyl, SO₂NH₂,SO₂N(H)C₁-C₆-alkyl, SO₂N(C₁-C₆-alkyl)₂, SO₂N(H)C₁-C₆-haloalkyl,SO₂N(C₁-C₆-haloalkyl)₂, SO₂N(C₁-C₆-alkyl)C₁-C₁-haloalkyl,—NH—SO₂—C₁-C₆-alkyl, —NH—SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-alkyl)-SO₂—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-alkyl, N(H)—CO—C₁-C₆-alkyl,N(H)—CO—C₁-C₆-haloalkyl, N(C₁-C₆-alkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-haloalkyl, SO₂—C₁-C₆-alkyl,SO₂—C₁-C₆-haloalkyl, NH₂, N(H)(C₁-C₆-alkyl), N(H)(C₁-C₆-haloalkyl),N(C₁-C₆-alkyl)₂, N(C₁-C₆-alkyl) (C₁-C₆-haloalkyl), andN(C₁-C₆-haloalkyl)₂; C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄ alkyl, hetaryl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(1d), andR^(a5), R^(b5) and R^(c5) have independently of one another one of themeanings mentioned for R^(a1), R^(b1) and R^(c1); R^(a6), R^(b6) andR^(c6) are independently of one another H, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3 substituentsindependently selected from OH, SH, COOH, CN, OCH₂COOH, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, COOH, C(O)OC₁-C₆-alkyl, C(O)OC₁-C₆-haloalkyl,C(O)O—C₂-C₆-alkenyl, C(O)O—C₂-C₆-alkynyl, C(O)O—C₃-C₇-cycloalkyl,C(O)O-aryl, C(O)O-hetaryl, CONH₂, CON(H)C₁-C₆-alkyl, CON(C₁-C₆-alkyl)₂,CON(H)C₁-C₆-haloalkyl, CON(C₁-C₆-haloalkyl)₂,CON(C₁-C₆-alkyl)C₁-C₆-haloalkyl, SO₂NH₂, SO₂N(H)C₁-C₆-alkyl,SO₂N(C₁-C₆-alkyl)₂, SO₂N(H)C₁-C₆-haloalkyl, SO₂N(C₁-C₆-haloalkyl)₂,SO₂N(C₁-C₆-alkyl) C₁-C₆-haloalkyl, —NH—SO₂—C₁-C₆-alkyl,—NH—SO₂—C₁-C₆-haloalkyl, —N(C₁-C₆-alkyl)-SO₂—C₁-C₆-alkyl,—N(C₁-C₆-alkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-alkyl, N(H)—CO—C₁-C₆-alkyl,N(H)—CO—C₁-C₆-haloalkyl, N(C₁-C₆-alkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-haloalkyl, SO₂—C₁-C₆-alkyl,SO₂—C₁-C₆-haloalkyl, NH₂, N(H)(C₁-C₆-alkyl), N(H)(C₁-C₆-haloalkyl),N(C₁-C₆-alkyl)₂, N(C₁-C₆-alkyl) (C₁-C₆-haloalkyl), andN(C₁-C₆-haloalkyl)₂; C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl,SO₂—C₁-C₆-alkyl, aryl, hetaryl, O-aryl, OCH₂-aryl, aryl-C₁-C₄-alkyl,hetaryl-C₁-C₄-alkyl, CO-aryl, CO-hetaryl, CO-(aryl-C₁-C₄-alkyl),CO-(hetaryl-C₁-C₄-alkyl), CO—O-aryl, CO—O-hetaryl,CO—O-(aryl-C₁-C₄-alkyl), CO—O-(hetaryl-C₁-C₄-alkyl), SO₂-aryl,SO₂-hetaryl, SO₂-(aryl-C₁-C₄-alkyl), or SO₂-(hetaryl-C₁-C₄-alkyl), wherearyl and hetaryl in the last 18 radicals mentioned are unsubstituted orhave 1, 2 or 3 substituents R^(1d), and R^(a7), R^(b7) and R^(c7) areindependently of one another H, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkyl which has 1, 2 or 3 substituents independently selected fromOH, SH, COOH, CN, OCH₂COOH, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₃-C₇-cycloalkyloxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, COOH,C(O)OC₁-C₆-alkyl, C(O)OC₁-C₆-haloalkyl, C(O)O—C₂-C₆-alkenyl,C(O)O—C₂-C₆-alkynyl, C(O)O—C₃-C₇-cycloalkyl, C(O)O-aryl, C(O)O-hetaryl,CONH₂, CON(H)C₁-C₆-alkyl, CON(C₁-C₆-alkyl)₂, CON(H)C₁-C₆-haloalkyl,CON(C₁-C₆-haloalkyl)₂, CON(C₁-C₆-alkyl)C₁-C₆-haloalkyl, SO₂NH₂,SO₂N(H)C₁-C₆-alkyl, SO₂N(C₁-C₆-alkyl)₂, SO₂N(H)C₁-C₆-haloalkyl,SO₂N(C₁-C₆-haloalkyl)₂, SO₂N(C₁-C₆-alkyl) C₁-C₆-haloalkyl,—NH—SO₂—C₁-C₆-alkyl, —NH—SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-alkyl)-SO₂—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-haloalkyl,—N(C₁-C₆-haloalkyl)-SO₂—C₁-C₆-alkyl, N(H)—CO—C₁-C₆-alkyl,N(H)—CO—C₁-C₆-haloalkyl, N(C₁-C₆-alkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-alkyl,N(C₁-C₆-haloalkyl)-CO—C₁-C₆-haloalkyl, SO₂—C₁-C₆-alkyl,SO₂—C₁-C₆-haloalkyl, NH₂, N(H)(C₁-C₆-alkyl), N(H)(C₁-C₆-haloalkyl),N(C₁-C₆-alkyl)₂, N(C₁-C₆-alkyl) (C₁-C₆-haloalkyl), andN(C₁-C₆-haloalkyl)₂; C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, aryl-C₁-C₄ alkyl, hetaryl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(1d), orthe two radicals R^(a6) and R^(a7), or R^(b6) and R^(b7), or R^(c6) andR^(c7), form together with the N atom a 3- to 7-membered, optionallysubstituted nitrogen heterocycle which may optionally have 1, 2 or 3further different or identical heteroatoms selected from the groupconsisting of O, N, and S as ring members, or two radicals R^(1b) orR^(1c) bonded to adjacent C atoms form together with the C atoms towhich they are bonded a 4-, 5-, 6- or 7-membered, optionally substitutedcarbocycle or an optionally substituted heterocycle which has 1, 2 or 3different or identical heteroatoms from the group of O, N, and S as ringmembers; R^(1d) is selected from halogen, OH, SH, NO₂, COOH, C(O)NH₂,CHO, CN, NH₂, OCH₂COOH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, CO—C₁-C₆-alkyl,CO—O—C₁-C₆-alkyl, NH—C₁-C₆-alkyl, NHCHO, NH—C(O)C₁-C₆-alkyl, andSO₂—C₁-C₆-alkyl; R² is C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,where a CH₂ group in the cycloalkyl moiety of the last two radicalsmentioned may be replaced by O, NH, or S, or two adjacent C atoms mayform a double bond, where the cycloalkyl moiety may additionally have 1,2, 3 or 4 R^(2a) radicals; aryl, O-aryl, O—CH₂-aryl, hetaryl,aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, hetaryl-C₁-C₄ alkyl orhetaryl-C₂-C₆-alkenyl, where aryl and hetaryl in the last 8 radicalsmentioned may be unsubstituted or carry 1, 2, 3 or 4 identical ordifferent R^(2b) radicals; where R^(2a) has one of the meaningsindicated for R^(1b), and R^(2b) has one of the meanings indicated forR^(1c); R^(3a) and R^(3b) are independently of one another hydroxy orC₁-C₄-alkoxy, or together with the carbon atom to which they are bondedare C═O; or R^(3a) and R^(3b) together form a moiety S-Alk-S, O-Alk-S orO-Alk-O, wherein Alk is linear C₂-C₅-alkandiyl, which may beunsubstituted or substituted with 1, 2, 3 or 4 radicals selected fromC₁-C₄-alkyl or halogen; X is hydrogen or a radical of the formulaeC(═O)—O—R^(x1), C(═O)—NR^(x2)R^(x3),C(═O)—N(R^(x4))—(C₁-C₆-alkylene)-NR^(x2)R^(x3) orC(═O)—N(R^(x4))NR^(x2)R^(x3), in which R^(x1) is hydrogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3 substituents R^(xa),C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, where alkyl, alkenyl, alkoxy, alkynyl,cycloalkyl, heterocycloalkyl in the last 6 radicals mentioned areunsubstituted or have 1, 2 or 3 substituents R^(xa), or aryl,aryl-C₁-C₄-alkyl, hetaryl or hetaryl-C₁-C₄-alkyl, where aryl and hetarylin the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3substituents R^(xd), R^(x2) is H, OH, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkyl which has 1, 2 or 3 substituents R^(xa), C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄ alkyl,CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, or O—C₁-C₆-alkyl,where alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycloalkylin the last 10 radicals mentioned are unsubstituted or have 1, 2 or 3substituents Rx, aryl, O-aryl, O—CH₂-aryl, hetaryl, O—CH₂-hetaryl,aryl-C₁-C₄-alkyl, hetaryl-C₁-C₄-alkyl, CO-aryl, CO-hetaryl,CO-(aryl-C₁-C₄-alkyl), CO-(hetaryl-C₁-C₄ alkyl), CO—O-aryl,CO—O-hetaryl, CO—O-(aryl-C₁-C₄-alkyl), CO—O-(hetaryl-C₁-C₄-alkyl),SO₂-aryl, SO₂-hetaryl, SO₂-(aryl-C₁-C₄-alkyl) orSO₂-(hetaryl-C₁-C₄-alkyl), where aryl and hetaryl in the last 19radicals mentioned are unsubstituted or have 1, 2 or 3 substituentsR^(xd), R^(x3) is H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl which has1, 2 or 3 substituents R^(xa), C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, wherealkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl in thelast 6 radicals mentioned are unsubstituted or have 1, 2 or 3substituents R^(xa), aryl, aryl-C₁-C₄-alkyl, hetaryl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(xd), orthe two radicals R^(x2) and R^(x3) form together with the N atom a 3- to7-membered nitrogen heterocycle which may optionally have 1, 2 or 3further different or identical heteroatoms selected from the groupconsisting of O, N, and S as ring members, and which may have 1, 2 or 3substituents R^(xb), and R^(x4) is H, OH, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3 substituents R^(xa),C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄ alkyl, CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, orSO₂—C₁-C₆-alkyl, where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl,heterocycloalkyl in the last 9 radicals mentioned are unsubstituted orhave 1, 2 or 3 substituents R^(xa), aryl, O-aryl, O—CH₂-aryl, hetaryl,aryl-C₁-C₄-alkyl, hetaryl-C₁-C₄-alkyl, CO-aryl, CO-hetaryl,CO-(aryl-C₁-C₄-alkyl), CO-(hetaryl-C₁-C₄-alkyl), CO—O-aryl,CO—O-hetaryl, CO—O-(aryl-C₁-C₄-alkyl), CO—O-(hetaryl-C₁-C₄-alkyl),SO₂-aryl, SO₂-hetaryl, SO₂-(aryl-C₁-C₄-alkyl), orSO₂-(hetaryl-C₁-C₄-alkyl), where aryl and hetaryl in the last 18radicals mentioned are unsubstituted or have 1, 2 or 3 substituentsR^(xd), and where R^(xa) has one of the meanings indicated for R^(1a),R^(xb) has one of the meanings indicated for R^(1b), and R^(xd) has oneof the meanings indicated for R^(1d); Y¹, Y², Y³ or Y⁴ are CR^(y), orone or two of the variables Y¹, Y², Y³ or Y⁴ are a nitrogen atom, andthe remaining variables Y¹, Y², Y³ or Y⁴ are CR^(y); R^(y) is selectedindependently of one another from hydrogen, OH, SH, halogen, NO₂, NH₂,CN, CF₃, CHF₂, CH₂F, O—CF₃, O—CHF₂, O—CH₂F, COOH, OCH₂COOH, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-alkylthio, where the last4 radicals mentioned may be partly or completely halogenated and/or have1, 2 or 3 substituents R^(ya), C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-cycloalkyl-O, where the cycloalkylmoiety in the last three radicals mentioned may have 1, 2, 3 or 4 R^(yb)radicals, and where 1 or 2 CH₂-groups in the cycloalkyl moiety may bereplaced by O, NH or S, aryl, hetaryl, O-aryl, CH₂-aryl, or O—CH₂-aryl,where the last 4 radicals mentioned are unsubstituted in the aryl moietyor may carry 1, 2, 3 or 4 radicals selected from the group consisting ofR^(yd), COOR^(y1), CONR^(y2)R^(y3), SO₂NR^(y2)R^(y3), —NH—SO₂—R^(y4),NH—CO—R^(y5), SO₂—R^(y4), —(CH)_(p)—NR^(y6)R^(y7) with p=0, 1, 2, 3, 4,5 or 6, and O—(CH₂)_(q)—NR^(y6)R^(y7) with q=2, 3, 4, 5 or 6; or twoR^(y) radicals bonded to adjacent C atoms form together with the C atomsto which they are bonded a 4-, 5-, 6- or 7-membered, optionallysubstituted carbocycle or an optionally substituted heterocycle whichhas 1, 2 or 3 different or identical heteroatoms selected from the groupconsisting of O, N, and S as ring members, where R^(ya) has one of themeanings indicated for R^(1a), R^(yb) has one of the meanings indicatedfor R^(1b), R^(yd) has one of the meanings indicated for R^(1d), R^(y1)has one of the meanings indicated for R^(c1), R^(y2) has one of themeanings indicated for R^(c2), R^(y3) has one of the meanings indicatedfor R^(c3), R^(y4) has one of the meanings indicated for R^(c4), R^(y5)has one of the meanings indicated for R^(c5), R^(y6) has one of themeanings indicated for R^(c6), and R^(y7) has one of the meaningsindicated for R^(c7); W is a radical of the formulae W1 or W2:

in which * means the linkage to the 6-membered aromatic ring, and #means the linkage to R², m is 0 or 1, Q is O, S or NR^(ww), R^(w) isselected from OH, SH, halogen, NO₂, NH₂, CN, COOH, OCH₂COOH,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-alkylthio,where the last 4 radicals mentioned may be partly or completelyhalogenated and/or have 1, 2 or 3 substituents R^(wa), C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-cycloalkyloxy, where the cycloalkylmoiety of the last three radicals mentioned may have 1, 2, 3 or 4radicals R^(wb), aryl, O-aryl, O—CH₂-aryl, or hetaryl, where the lastfour radicals mentioned are unsubstituted in the aryl moiety or maycarry 1, 2, 3 or 4 radicals selected from the group consisting ofR^(wd), COOR^(w1), CONR^(w2)R^(w3), SO₂NR^(w2)R^(w3),NR^(w2)—SO₂—R^(w4), NR^(w2)—CO—R^(w5), SO₂—R^(w4),—(CH₂)_(p)—NR^(w6)R^(w7) with p=0, 1, 2, 3, 4, 5 or 6, andO—(CH₂)_(q)—NR^(w6)R^(w7) with q=2, 3, 4, 5 or 6; or two R^(w) radicalsbonded to adjacent C atoms form together with the C atoms to which theyare bonded a 4, 5, 6 or 7-membered, optionally substituted carbocycle oran optionally substituted heterocycle which has 1, 2 or 3 different oridentical heteroatoms selected from the group consisting of O, N, and Sas ring members, where R^(wa) has one of the meanings indicated forR^(1a), R^(wb) has one of the meanings indicated for R^(1b), R^(wd) hasone of the meanings indicated for R^(1d), R^(w1) has one of the meaningsindicated for R^(c1), R^(w2) has one of the meanings indicated forR^(c2), R^(w3) has one of the meanings indicated for R^(c3), R^(w4) hasone of the meanings indicated for R^(c4), R^(w5) has one of the meaningsindicated for R^(c5), R^(w6) has one of the meanings indicated forR^(c6), R^(w7) has one of the meanings indicated for R^(c7), R^(ww) isselected from H, OH, NH₂, CN, CF₃, CHF₂, CH₂F, O—CF₃, O—CHF₂, O—CH₂F,COOH, OCH₂COOH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,where the last 4 radicals mentioned may be partly or completelyhalogenated and/or have 1, 2 or 3 substituents R^(wa), C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-cycloalkyloxy, where the cycloalkylmoiety of the last three radicals mentioned may have 1, 2, 3 or 4radicals R^(wb), aryl, O-aryl, O—CH₂-aryl, or hetaryl, where the lastfour radicals mentioned are unsubstituted in the aryl moiety or maycarry 1, 2, 3 or 4 radicals selected from the group consisting ofR^(wd), COOR^(w1), CONR^(w2)R^(w3), SO₂NR^(w2)R^(w3),NR^(w2)—SO₂—R^(w4), NR^(w2)—CO—R^(w5), SO₂—R^(w4),—(CH₂)_(p)—NR^(w6)R^(w7) with p=0, 1, 2, 3, 4, 5 or 6, andO—(CH₂)_(q)—NR^(w6)R^(w7) with q=2, 3, 4, 5 or 6; or W forms togetherwith R² a radical of the formula W3:

in which * means the linkage to the 6-membered aromatic ring, Q has oneof the meanings indicated for Q in formula W1, k is 0, 1 or 2, andR^(w*) has one of the meanings indicated for R^(w), or a tautomerthereof, or a pharmaceutically suitable salt thereof.
 35. Thecarboxamide compound of claim 34, in which m is
 0. 36. The carboxamidecompound of claim 34, in which X in the formula I is aC(═O)—NR^(x2)R^(x3) radical in which R^(x2) is H, OH, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkyl which has 1, 2 or 3 substituents R^(xa),C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₄-alkyl, C₃-C₇-heterocycloalkyl-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, aryl, hetaryl, aryl-C₁-C₄-alkyl, orhetaryl-C₁-C₄-alkyl, where aryl and hetaryl in the last 4 radicalsmentioned are unsubstituted or have 1, 2 or 3 substituents R^(xd), andR^(x3) is H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, or C₁-C₆-alkyl which has 1, 2or 3 substituents R^(xa), or NR^(x2)R^(x3) is a nitrogen heterocycle ofthe following formulae:

in which R^(x5) is hydrogen or has the meaning indicated in claim 34 forR^(xb).
 37. The carboxamide compound of claim 36, in which X isC(O)—NH₂.
 38. The carboxamide compound as claimed in claim 34, in whichR¹ is selected from: C₃-C₁₀-alkyl which is unsubstituted or may bepartly or completely halogenated and/or have 1, 2 or 3 substituentsR^(1a), phenyl-C₁-C₄-alkyl, and hetaryl-C₁-C₄-alkyl, where phenyl andhetaryl in the last 2 radicals mentioned may be unsubstituted or carry1, 2, 3 or 4 identical or different radicals R^(1c).
 39. The carboxamidecompound as claimed in claim 34, in which R² is selected from: aryl, andhetaryl, where aryl and hetaryl in the last 2 radicals mentioned may beunsubstituted or carry 1, 2, 3 or 4 identical or different radicalsR^(2b).
 40. The carboxamide compound of claim 39, in which R² is phenyl,which is unsubstituted or carries 1, 2, 3 or 4 identical or differentradicals R^(2b).
 41. The carboxamide compound of claim 34, in which Y⁴is N.
 42. The carboxamide compound of claim 41, in which Y¹, Y² and Y³are CR^(Y), wherein R^(Y) may be identical or different and are asdefined in claim
 34. 43. The carboxamide compound of claim 41, in whichY¹ is N and Y² and Y³ are CR^(Y), or Y² is N and Y¹ and Y³ are CR^(Y),wherein R^(Y) may be identical or different and are as defined in claim34.
 44. The carboxamide compound of claim 34, in which Y¹, Y², Y³ and Y⁴are CR^(Y), wherein R^(Y) may be identical or different and are asdefined in claim
 34. 45. The carboxamide compound of claim 34, in whichR^(3a) and R^(3b) are hydroxy or together with the carbon atom to whichthey are bonded are C═O.
 46. The carboxamide compound of claim 34, whichcorresponds to the formula I-A,

in which m, X, Q, Y¹, Y², Y³, Y⁴, R¹, R², R^(3a), R^(3b), and R^(w) havethe aforementioned meanings, or a tautomer thereof, or apharmaceutically suitable salt thereof.
 47. The carboxamide compound asclaimed of claim 34, which corresponds to the formula I-B,

in which m, X, Q, Y¹, Y², Y³, Y⁴, R¹, R², R^(3a), R^(3b), and R^(w) havethe aforementioned meanings, or a tautomer thereof, or apharmaceutically suitable salt thereof.
 48. The carboxamide compound ofclaim 34, which corresponds to the formula I-C,

in which m, X, Q, Y¹, Y², Y³, Y⁴, R¹, R^(3a), R^(3b), and R^(w) have theaforementioned meanings, or a tautomer thereof, or a pharmaceuticallysuitable salt thereof.
 49. The carboxamide compound of claim 34, whichcorresponds to the formula I-a,

in which X, W, R¹, R², R^(3a), and R^(3b) have the aforementionedmeanings, and wherein n is 0, 1 or 2 and R^(yy) has one of the meaningsindicated for R^(y) which are different from hydrogen, or a tautomerthereof, or a pharmaceutically suitable salt thereof.
 50. Thecarboxamide compound of claim 34, which corresponds to the formula I-b,

in which X, W, R¹, R², R^(3a), and R^(3b) have the aforementionedmeanings, and wherein n is 0, 1 or 2 and R^(yy) has one of the meaningsindicated for R^(y) which are different from hydrogen, or a tautomerthereof, or a pharmaceutically suitable salt thereof.
 51. Thecarboxamide compound of claim 34, which corresponds to the formulae I-cor I-d,

in which X, W, R¹, R², R^(3a), and R^(3b) have the aforementionedmeanings, and wherein n is 0, 1 or 2 and R^(yy) has one of the meaningsindicated for R^(y) which are different from hydrogen, or a tautomerthereof, or a pharmaceutically suitable salt thereof.
 52. Thecarboxamide compounds of the formula I-a of claim 49, wherein W is aradical W1.
 53. The carboxamide compounds of the formula I-a of claim49, wherein W is a radical W2.
 54. The carboxamide compounds of theformula I-a of claim 49, wherein W—R² is a radical W3.
 55. Thecarboxamide compound of claim 34, wherein Q is S.
 56. The carboxamidecompound of claim 34, wherein Q is O or NH.
 57. The carboxamide compoundof claim 34, which has the S configuration at the carbon atom carryingthe group R¹.
 58. The carboxamide compound of claim 34, which areselected from the group consisting of:N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(5-phenyl-1H-imidazol-2-yl)pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-{4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyl-1,3-thiazol-2-yl)pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]pyridine-3-carboxamide;N-(1-amino-1,2-dioxoheptan-3-yl)-2-(4-phenyl-1,3-thiazol-2-yl)nicotinamide;N-(1-amino-1,2-dioxoheptan-3-yl)-2-(4-phenyl-1,3-thiazol-2-yl)benzamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyl-1,3-thiazol-2-yl)benzamide;N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyl-1,3-thiazol-2-yl)nicotinamide;N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenylthiazol-2-yl)nicotinamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-phenyloxazol-2-yl)nicotinamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-{2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyl-1,3-thiazol-4-yl)pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(2-chlorophenyl)-1,3-thiazol-4-yl]pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[2-(naphthalen-2-yl)-1,3-thiazol-4-yl]pyridine-3-carboxamide;N-(1-amino-1,2-dioxoheptan-3-yl)-2-(2-phenylthiazol-4-yl)nicotinamide;N-(1-amino-1,2-dioxoheptan-3-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyl-1,3-thiazol-4-yl)benzamide;N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide;N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(2-phenyloxazol-4-yl)nicotinamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1H-benzimidazol-2-yl)pyridine-3-carboxamide;N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1,3-benzothiazol-2-yl)pyridine-3-carboxamide;andN-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(1,3-benzo[d]oxazol-2-yl)pyridine-3-carboxamide;or a tautomer thereof, or a pharmaceutically suitable salt thereof. 59.A medicament comprising at least one carboxamide compound of claim 34, atautomer or a pharmaceutically suitable salt thereof, and one or moresuitable excipients/drug carriers.
 60. A method for the therapeuticand/or prophylactic treatment of a mammal requiring a treatment, byadministering an effective amount of at least one compound of claim 34,for the treatment of a disorder, of a condition or of an impairmentselected from neurodegenerative disorders or impairments,neurodegenerative disorders occurring as a result of a chronic brainsupply deficit, an ischemia or a trauma is involved, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, multiple sclerosis and concomitant damage to thenervous system, epilepsy, pain, infectious diseases, such as malaria,slow-channel congenital myasthenic syndrome, excitotoxic DNAfragmentation via mitochondrial pathways, damage to the heart followingcardiac ischemias, skeletal muscle damage, muscular dystrophies,necrotic processes in dystrophic muscles, damage resulting fromproliferation of smooth muscle cells, coronary vasospasms, cerebralvasospasms, macular degeneration, cataracts of the eyes, restenosis ofthe blood vessels following angioplasty, disorders or an impairmentassociated with an elevated interleukin-1, TNF or Aβ level, a disorder,an impairment or a condition which is associated with an elevatedcalpain activity, damages to the kidney following renal ischemias andkidney diseases, such as glomerulonephritis or diabetic nephropathy,chemotherapy of tumors and metastasis thereof, and HIV patients.